Analyte sensor

ABSTRACT

Systems and methods of use for continuous analyte measurement of a host&#39;s vascular system are provided. In some embodiments, a continuous glucose measurement system includes a vascular access device, a sensor and sensor electronics, the system being configured for insertion into communication with a host&#39;s circulatory system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/691,424 filed Mar. 26, 2007. U.S. application Ser. No. 11/691,424 isa continuation-in-part of U.S. application Ser. No. 11/543,396 filedOct. 4, 2006; and is a continuation-in-part of U.S. application Ser. No.11/543,490 filed Oct. 4, 2006; and is a continuation-in-part of U.S.application Ser. No. 11/543,404 filed Oct. 4, 2006. The disclosures ofeach of the above-referenced applications are hereby expresslyincorporated by reference in their entirety and are hereby expresslymade a portion of this application.

FIELD OF THE INVENTION

The preferred embodiments relate generally to systems and methods formeasuring an analyte in a host.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which can cause anarray of physiological derangements associated with the deterioration ofsmall blood vessels, for example, kidney failure, skin ulcers, orbleeding into the vitreous of the eye. A hypoglycemic reaction (lowblood sugar) can be induced by an inadvertent overdose of insulin, orafter a normal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a person admitted to a hospital for certain conditions(with or without diabetes) is tested for blood sugar level by a singlepoint blood glucose meter, which typically requires uncomfortable fingerpricking methods or blood draws and can produce a burden on the hospitalstaff during a patient's hospital stay. Due to the lack of convenience,blood sugar glucose levels are generally measured as little as once perday or up to once per hour. Unfortunately, such time intervals are sofar spread apart that hyperglycemic or hypoglycemic conditionsunknowingly occur, incurring dangerous side effects. It is not onlyunlikely that a single point value will not catch some hyperglycemic orhypoglycemic conditions, it is also likely that the trend (direction) ofthe blood glucose value is unknown based on conventional methods. Thisinhibits the ability to make educated insulin therapy decisions.

A variety of sensors are known that use an electrochemical cell toprovide output signals by which the presence or absence of an analyte,such as glucose, in a sample can be determined. For example, in anelectrochemical cell, an analyte (or a species derived from it) that iselectro-active generates a detectable signal at an electrode, and thissignal can be used to detect or measure the presence and/or amountwithin a biological sample. In some conventional sensors, an enzyme isprovided that reacts with the analyte to be measured, and the byproductof the reaction is qualified or quantified at the electrode. An enzymehas the advantage that it can be very specific to an analyte and also,when the analyte itself is not sufficiently electro-active, can be usedto interact with the analyte to generate another species which iselectro-active and to which the sensor can produce a desired output. Inone conventional amperometric glucose oxidase-based glucose sensor,immobilized glucose oxidase catalyses the oxidation of glucose to formhydrogen peroxide, which is then quantified by amperometric measurement(for example, change in electrical current) through a polarizedelectrode.

SUMMARY OF THE INVENTION

In a first aspect, a system for measuring an analyte is provided, thesystem comprising: a vascular access device configured to be incommunication with a circulatory system of a host; and an analyte sensorconfigured to reside within the vascular access device, wherein theanalyte sensor is configured to measure a concentration of an analytewithin the circulatory system.

In an embodiment of the first aspect, the system further comprises aflow control device.

In an embodiment of the first aspect, the flow control device comprisesat least one of a pump and a valve.

In an embodiment of the first aspect, the flow control device isconfigured to draw back a sample from the circulatory system.

In an embodiment of the first aspect, the sample has a volume of about500 microliters or less.

In an embodiment of the first aspect, the sample has a volume of about50 microliters or less.

In an embodiment of the first aspect, the flow control device isconfigured to draw back the sample at a rate of from about 0.001 ml/minto about 2.0 ml/min.

In an embodiment of the first aspect, the rate is from about 0.01 ml/minto about 1.0 ml/min.

In an embodiment of the first aspect, the flow control device isconfigured to draw back a sample substantially no farther than thevascular access device.

In an embodiment of the first aspect, the flow control device isconfigured to draw back a sample substantially no farther than a planedefined by skin of the host.

In an embodiment of the first aspect, the flow control device isconfigured to infuse a fluid through the vascular access device and intothe circulatory system.

In an embodiment of the first aspect, the flow control device isconfigured to infuse the fluid at a rate such that a temperature of thefluid substantially equilibrates with a temperature of the host.

In an embodiment of the first aspect, the fluid has a knownconcentration of the analyte and the sensor comprises electronicsconfigured to measure a signal associated with the known concentrationof the analyte.

In an embodiment of the first aspect, an in vivo portion of the analytesensor has a width of less than about 0.020 inches.

In an embodiment of the first aspect, the in vivo portion of the analytesensor has a width of less than about 0.010 inches.

In an embodiment of the first aspect, the vascular access devicecomprises a single lumen.

In an embodiment of the first aspect, the vascular access devicecomprises an 18 gauge or smaller catheter.

In an embodiment of the first aspect, the vascular access devicecomprises a 22 gauge or smaller catheter.

In an embodiment of the first aspect, the vascular access devicecomprises a sidewall and at least one orifice disposed within thesidewall, wherein the orifice is configured to allow blood to passtherethrough.

In an embodiment of the first aspect, the orifice is configured to allowblood to contact at least a portion of the sensor.

In an embodiment of the first aspect, the sensor comprises a tip, andwherein the tip of the sensor is disposed within the vascular accessdevice.

In an embodiment of the first aspect, the tip of the sensor is disposedabout 2 cm or less from a tip of the vascular access device.

In an embodiment of the first aspect, at least a portion of the sensoris configured to extend out of the vascular access device.

In an embodiment of the first aspect, at least a portion of the sensoris configured to intermittently protrude out of the vascular accessdevice.

In an embodiment of the first aspect, the analyte sensor furthercomprises a bioinert material or a bioactive agent incorporated thereinor thereon.

In an embodiment of the first aspect, the bioactive agent comprises atleast one agent selected from the group consisting of vitamin Kantagonists, heparin group anticoagulants, platelet aggregationinhibitors, enzymes, direct thrombin inhibitors, Dabigatran,Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban.

In a second aspect, a system for measuring an analyte is provided, thesystem comprising: a vascular access device configured to be incommunication with a circulatory system of a host; an analyte sensorconfigured to reside within the vascular access device, wherein theanalyte sensor is configured to measure a concentration of an analytewithin the circulatory system; and a flow control device.

In an embodiment of the second aspect, the flow control device comprisesa valve.

In an embodiment of the second aspect, the valve comprises a firstdiscreet position and a second discreet position.

In an embodiment of the second aspect, the valve is configured to movebetween the first position and the second position over a time period offrom about 0.5 seconds to about 10.0 seconds.

In an embodiment of the second aspect, the system further comprisestubing fluidly connected to the valve, wherein the valve is configuredto meter a flow through the tubing at a predetermined flow rate.

In an embodiment of the second aspect, the predetermined flow rate isfrom about 0.001 ml/min to about 2.0 ml/min.

In an embodiment of the second aspect, the predetermined flow rate flowrate is from about 0.02 ml/min to about 0.35 ml/min.

In an embodiment of the second aspect, the system further comprisestubing connected to the valve, wherein the valve is configured such thatabout 500 microliters or less of a fluid passes through the tubingduring movement of the valve between the first position and the secondposition.

In an embodiment of the second aspect, the system is configured to pushfluid through the tubing during movement of the valve from the firstposition to the second position.

In an embodiment of the second aspect, the system is configured to drawback a sample into the tubing during movement of the valve from thesecond position to the first position.

In an embodiment of the second aspect, the valve is configured such thatabout 50 microliters or less of a fluid passes through the tubing duringthe movement of the valve between the first position and the secondposition.

In an embodiment of the second aspect, the system further comprises abag containing a fluid.

In an embodiment of the second aspect, the system further comprises aflow regulator configured to regulate a flow of the fluid.

In an embodiment of the second aspect, the system further comprises alocal analyzer.

In an embodiment of the second aspect, the local analyzer comprises apotentiostat.

In an embodiment of the second aspect, the local analyzer comprises adata processing module.

In an embodiment of the second aspect, the local analyzer comprises adata storage module.

In an embodiment of the second aspect, the system further comprises aremote analyzer.

In an embodiment of the second aspect, the remote analyzer comprises atouch screen.

In an embodiment of the second aspect, the remote analyzer is configuredto control the flow control device.

In an embodiment of the second aspect, the remote analyzer is detachablyoperably connected to a local analyzer.

In an embodiment of the second aspect, the remote analyzer comprises adata processing module.

In an embodiment of the second aspect, the remote analyzer comprises adata storage module.

In an embodiment of the second aspect, the flow control device comprisesa processor configured to control the flow control device, and whereinthe processor is operably connected to the remote analyzer.

In an embodiment of the second aspect, the flow control device comprisesa pump.

In a third aspect, a method for measuring a concentration of an analytein of a host is provided, the method comprising: a) providing an analytemeasuring system comprising a vascular access device, an analyte sensorconfigured measure an analyte concentration, and electronics operativelyconnected to the sensor and configured to generate a signal associatedwith the analyte concentration; wherein the analyte sensor is configuredto reside within the vascular access device; b) placing the vascularaccess device and sensor in fluid communication with the circulatorysystem; c) passing a reference solution past the analyte sensor andmeasuring a signal associated with an analyte concentration of thereference solution; and d) drawing back a sample from the circulatorysystem and measuring a signal associated with the analyte concentrationof the sample.

In an embodiment of the third aspect, the step of passing a referencesolution comprises passing the reference solution at a first flow rateof from about 0.001 ml/min to about 2 ml/min.

In an embodiment of the third aspect, the step of passing a referencesolution comprises passing the reference solution at a first flow rateof from about 0.02 ml/min to about 0.35 ml/min.

In an embodiment of the third aspect, the step of passing a referencesolution comprises allowing a temperature of the reference solution toequilibrate with a temperature of the host.

In an embodiment of the third aspect, the step of drawing back a samplecomprises drawing back a sample at a second flow rate of from about0.001 ml/min to about 2 ml/min.

In an embodiment of the third aspect, the step of drawing back a samplecomprises drawing back a sample at a second flow rate of from about 0.02ml/min to about 0.35 ml/min.

In an embodiment of the third aspect, the step of drawing back a samplecomprises substantially blocking mixing of the reference solution andthe sample.

In an embodiment of the third aspect, the second flow rate issubstantially equal to the first flow rate.

In an embodiment of the third aspect, the vascular access device is influid communication with a vein, the method further comprising a step ofkeeping the vein open by passing the reference solution past the sensorat a third flow rate.

In an embodiment of the third aspect, the third flow rate is less thanthe first flow rate.

In an embodiment of the third aspect, the third flow rate is from about1.0 ml/min.

In an embodiment of the third aspect, the third flow rate is from about0.02 ml/min to about 0.2 ml/min.

In an embodiment of the third aspect, the analyte measuring systemfurther comprises a flow control device, wherein the flow control deviceis configured to meter flow during steps c) and d).

In an embodiment of the third aspect, the flow control device comprisesa valve comprising a first discreet position and a second discreetposition.

In an embodiment of the third aspect, the step of passing a referencesolution comprises moving the valve from the first position to thesecond position.

In an embodiment of the third aspect, the step of passing a referencesolution comprises passing a solution volume of about 500 microliters orless during movement of the valve from the first position to the secondposition.

In an embodiment of the third aspect, the step of drawing back a samplecomprises moving the valve from the second position to the firstposition.

In an embodiment of the third aspect, the step of drawing back a samplecomprises drawing back a sample volume of about 500 microliters or lessduring movement of the valve from the second position to the firstposition.

In an embodiment of the third aspect, the step of drawing back a samplecomprises drawing back a sample volume of about 50 microliters or lessduring movement of the valve from the second position to the firstposition.

In an embodiment of the third aspect, the vascular access device is influid communication with a vein, the method further comprising a step ofkeeping the vein open by metering flow of the reference solution throughthe vascular access device at a predetermined rate.

In an embodiment of the third aspect, the step of metering the flow iscontrolled at least in part by a timing for the valve to move betweenthe first position and the second position.

In an embodiment of the third aspect, the step of drawing back thesample from the circulatory system comprises drawing back the samplesubstantially no farther than the vascular access device.

In an embodiment of the third aspect, the step of drawing back thesample from the circulatory system comprises drawing back the sampleinto the vascular access device substantially no farther than a planedefined by the skin of the host.

In an embodiment of the third aspect, the analyte is glucose, andwherein the step of measuring the concentration of the analyte comprisesmeasuring a glucose concentration.

In an embodiment of the third aspect, the flow control device comprisesa valve.

In an embodiment of the third aspect, the flow control device comprisesa pump.

In an embodiment of the third aspect, steps c) through d) are repeated.

In a fourth aspect, a method for measuring a concentration of an analytein a circulatory system of a host is provided, the method comprising: a)providing an analyte measuring system comprising a vascular accessdevice, an analyte sensor, a flow control device, a fluids bag, an IVtubing, and a processor, wherein the processor is operatively connectedto the flow control device and analyte sensor; b) inserting the vascularaccess device and the analyte sensor into fluid communication with thehost's circulatory system; c) injecting a first reference solution intothe IV tubing; d) coupling the fluids bag to the IV tubing, the fluidsbag comprising a second reference solution; and e) initiating theanalyte measuring system, wherein the processor is configured toauto-calibrate the analyte sensor without additional user interactionwith the system.

In an embodiment of the fourth aspect, the first reference solution hasa first known analyte concentration and wherein the second referencesolution comprises a second known reference solution.

In an embodiment of the fourth aspect, the system is configured toauto-calibrate the analyte sensor using the first reference solution andthe second reference solution.

In an embodiment of the fourth aspect, the system provides calibratedsensor data for at least about 24 hours prior to injection of anotherreference solution into the IV tubing.

In a fifth aspect, a system for monitoring analyte concentration in abiological sample of a host is provided, the system comprising: asubstantially continuous analyte sensor configured to produce a datasignal indicative of an analyte concentration in a host during exposureof the sensor to a biological sample; a reference solution having aknown analyte concentration, wherein the system is configured to exposethe sensor to the reference solution, and wherein the system isconfigured to produce a data signal indicative of an analyteconcentration in the reference solution during exposure of the sensor tothe reference solution; and a computer system comprising programmingconfigured to determine calibration information and to calibrate asignal associated with a biological sample therefrom, wherein thecalibration information comprises steady state information and transientinformation.

In an embodiment of the fifth aspect, the calibration information isdetermined from a signal associated with exposure of the sensor to thereference solution and a signal associated with exposure of the sensorto the biological sample.

In an embodiment of the fifth aspect, the steady state informationcomprises at least one of sensitivity information and baselineinformation.

In an embodiment of the fifth aspect, the steady state informationcomprises both sensitivity information and baseline information.

In an embodiment of the fifth aspect, the steady state informationcomprises information associated with a signal produced during exposureof the sensor to the reference solution.

In an embodiment of the fifth aspect, the reference solution comprises aknown analyte concentration of about zero, and wherein the steady stateinformation comprises baseline information about the sensor in thereference solution.

In an embodiment of the fifth aspect, the reference solution comprises aknown analyte concentration of more than zero, and wherein the steadystate information comprises sensitivity information about the sensor.

In an embodiment of the fifth aspect, the steady state calibrationinformation comprises reference data from an analyte sensor other thanthe substantially continuous analyte sensor.

In an embodiment of the fifth aspect, transient information comprises arate of change of a signal produced during exposure of the sensor to astep change in analyte concentration.

In an embodiment of the fifth aspect, the rate of change comprises arate change of a signal produced during exposure of the sensor to abiological sample of an unknown analyte concentration or an uncalibratedanalyte concentration.

In an embodiment of the fifth aspect, the rate of change comprises arate change of a signal produced during exposure of the sensor to abiological sample, and wherein the steady state information comprisesreference data from an analyte sensor other than the substantiallycontinuous analyte sensor.

In an embodiment of the fifth aspect, transient information comprises animpulse response of a signal produced during exposure of the sensor to astep change in analyte concentration.

In an embodiment of the fifth aspect, the impulse response is used todetermine an offset between a baseline measurement associated with thereference solution and a baseline measurement associated with abiological sample.

In an embodiment of the fifth aspect, the impulse response is used todetermine a time point of a steady state measurement during which ananalyte concentration can be obtained.

In an embodiment of the fifth aspect, the transient informationcomprises a comparison of steady state information and transientinformation for a plurality of time-spaced signals associated withbiological samples of unknown analyte concentration or uncalibratedanalyte concentration.

In an embodiment of the fifth aspect, the comparison of steady stateinformation and transient information is used to determine an offsetbetween a baseline measurement associated with the reference solutionand a baseline measurement associated with a biological sample.

In an embodiment of the fifth aspect, the system further comprisesprogramming to detect a shift in baseline or sensitivity based on acomparison of steady state information and transient information.

In an embodiment of the fifth aspect, the system further comprisesprogramming configured to initiate calibration of the signal to correctfor a shift in at least one of baseline and sensitivity based on acomparison of steady state information and transient information.

In an embodiment of the fifth aspect, the system further comprisesprogramming configured to calibrate of the signal to correct for a shiftin at least one of baseline and sensitivity based on a comparison ofsteady state information and transient information.

In an embodiment of the fifth aspect, the programming is configured tocalibrate a signal is configured to perform at least one of initialcalibration and update calibration.

In an embodiment of the fifth aspect, the analyte sensor is a glucosesensor.

In a sixth aspect, a system for monitoring analyte concentration in abiological sample of a host is provided, the system comprising: asubstantially continuous analyte sensor configured to produce a datasignal indicative of an analyte concentration in a host during exposureof the sensor to a biological sample; a reference solution having aknown analyte concentration, wherein the system is configured to exposethe sensor to the reference solution, and wherein the system isconfigured to produce a data signal indicative of an analyteconcentration in the reference solution during exposure of the sensor tothe reference solution; and a computer system comprising programmingconfigured to determine calibration information and to calibrate asignal associated with a biological sample therefrom, wherein thecalibration information is determined from a signal associated withexposure of the sensor to the reference solution and a signal associatedwith exposure of the sensor a biological sample, wherein the biologicalsample is of unknown analyte concentration or uncalibrated analyteconcentration.

In an embodiment of the sixth aspect, calibration information comprisessteady state information and transient information

In an embodiment of the sixth aspect, the steady state informationcomprises at least one of sensitivity information and baselineinformation

In an embodiment of the sixth aspect, transient information comprises arate of change of the sensor's signal responsive to exposure of thesensor to a change in analyte concentration

In an embodiment of the sixth aspect, transient information comprises arate of change of a signal produced during exposure of the sensor to astep change in analyte concentration.

In an embodiment of the sixth aspect, the analyte sensor is a glucosesensor.

In a seventh aspect, a system for monitoring analyte concentration in abiological sample of a host is provided, the system comprising: asubstantially continuous analyte sensor configured to produce a datasignal indicative of an analyte concentration in a host during exposureof the sensor to a biological sample; a reference solution having aknown analyte concentration, wherein the system is configured to exposethe sensor to the reference solution, and wherein the system isconfigured to produce a data signal indicative of an analyteconcentration in the reference solution during exposure of the sensor tothe reference solution; and a computer system comprising programmingconfigured to determine calibration information and calibrate a signalassociated with a biological sample therefrom, wherein the calibrationinformation is determined from at least one of a signal associated withexposure of the sensor to the reference solution and a signal associatedwith exposure of the sensor to a biological sample, wherein thebiological sample is of unknown analyte concentration or uncalibratedanalyte concentration.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to diagnose a condition of at least oneof the sensor and the host responsive to calibration information.

In an embodiment of the seventh aspect, calibration informationcomprises baseline information, and wherein the system comprisesprogramming configured to determine an offset between a baselineassociated with a reference solution and a baseline associated with abiological sample.

In an embodiment of the seventh aspect, the offset is determined byprocessing an impulse response of the sensor's signal during exposure ofthe sensor to a step change in analyte concentration.

In an embodiment of the seventh aspect, the offset is determined by acomparison of steady state information and transient information for aplurality of time-spaced samples of a biological sample of unknownanalyte concentration or uncalibrated analyte concentration.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to detect an interfering speciesresponsive to a change in the offset above a predetermined amount.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to diagnose a condition of the host'smetabolic processes responsive to a change in the offset above apredetermined amount.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to display or transmit a messageassociated with the host's condition responsive to diagnosing thecondition.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to diagnose an error and fail-saferesponsive to a change in the offset above a predetermined amount.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to recalibrate the sensor responsive toa change in the offset above a predetermined amount.

In an embodiment of the seventh aspect, calibration informationcomprises sensitivity information, and wherein the system comprisesprogramming configured to diagnose an error responsive to a change insensitivity above a predetermined amount.

In an embodiment of the seventh aspect, the computer system furthercomprises programming configured to calculate an impulse response of asignal produced during exposure of the sensor to a step change inanalyte concentration, and wherein a time constant for the step changeis determined from the time of the peak impulse response.

In an embodiment of the seventh aspect, the step of calculating animpulse response is repeated more than one time, and wherein thecomputer system further comprises programming configured to diagnose asensor condition or error responsive to a change in the time constantsassociated with the plurality of step changes above a predeterminedthreshold.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of one embodiment of an analyte sensorsystem, including a vascular access device (e.g., a catheter), a sensor,a fluid connector, and a protective sheath.

FIG. 1B is a side view of the analyte sensor system of FIG. 1A, showingthe protective sheath removed.

FIG. 1C1 is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1C2 is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1D is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1E is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 2A is a perspective view of another embodiment of the analytesensor system, including a catheter with a sensor integrally formedthereon.

FIG. 2B is a perspective view of the analyte sensor system of FIG. 2A.

FIG. 2C is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2D is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2E is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having two electrodes disposed onthe catheter.

FIG. 2F is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having one electrode disposed onthe catheter.

FIG. 3A is a perspective view of a first portion of one embodiment of ananalyte sensor.

FIG. 3B is a perspective view of a second portion of the analyte sensorof FIG. 3A.

FIG. 3C is a cross section of the analyte sensor of FIG. 3B, taken online C-C.

FIG. 4 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

FIG. 5 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

FIG. 6 is a schematic of an integrated sensor system.

FIG. 7 is a block diagram of an integrated sensor system

FIGS. 8A through 8C are schematic illustrations of a flow control devicein one exemplary embodiment, including is relative movement/positionsand the consequential effect on the flow of fluids through thesensor/catheter inserted in a host.

FIG. 9 is a cut-away illustration of one exemplary embodiment of acatheter implanted in a host's vessel.

FIG. 10 is a graph that schematically illustrates a signal producedduring exposure of the sensor to a step change in analyte concentration,in one exemplary embodiment.

FIG. 11 is a graph that schematically illustrates a derivative of thestep response shown in FIG. 9.

FIG. 12 is a graph that illustrates level vs. rate for a plurality oftime-spaced signals associated with exposure of the sensor to biologicalsamples of unknown or uncalibrated analyte concentration.

FIG. 13 is a graphical representation showing exemplary glucose sensordata and corresponding blood glucose values over time in a pig.

FIG. 14 is a graphical representation showing exemplary calibratedglucose sensor data (test) and corresponding blood glucose values (YSIcontrol) over time in a human.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the preferred embodiments.

DEFINITIONS

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes caninclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensing regions, devices, and methods is glucose.However, other analytes are contemplated as well, including but notlimited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acidprofiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine,phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine;arabinitol enantiomers; arginase; benzoylecgonine (cocaine);biotimidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4;ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatinekinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylatorpolymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cysticfibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphatedehydrogenase, hemoglobin A, hemoglobin S. hemoglobin C, hemoglobin D,hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenyloin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, AdvancedGlycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).

The term “sensor break-in” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the time (after implantation)in which the sensor's signal level becomes substantially representativeof the analyte (e.g., glucose) concentration (e.g., where the currentoutput from the sensor is stable relative to the glucose level). Thesignal may not be ‘flat’ at that point (e.g., when the sensor hasbroken-in), but, in general, variation in the signal level at that pointis due to a change in the analyte (e.g., glucose) concentration. Thus“sensor break-in” generally refers to the time required for the sensor'soutput signal to provide a substantially linear response to the analyteconcentration (e.g., glucose level). In some preferred embodiments,sensor break-in occurs prior to obtaining a meaningful calibration ofthe sensor output. In some embodiments, sensor break-in generallyincludes both electrochemical break-in and membrane break-in.

The term “membrane break-in” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an amount of time necessaryfor the membrane to equilibrate to its surrounding environment (e.g.,physiological environment in vivo).

The term “electrochemical break-in” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the time, aftersensor insertion in vitro and/or in vivo, at which the current outputfrom the sensor settles to a stable value following the application ofthe potential to the sensor. Generally, prior to this time, the outputmay not be clinically useful. Accordingly, reductions in the length oftime required to reach electrochemical break-in can be desirable, forexample, in acute care environments.” Numerous methods of acceleratingelectrochemical break-in can be used, such as, but not limited to,configuring the sensor electronics to aid in decreasing the break-intime of the sensor by applying different voltage settings (for example,starting with a higher voltage setting and then reducing the voltagesetting). Additional methods of accelerating sensor break-in time aredescribed in U.S. Pat. No. 5,411,647, for example, which is incorporatedherein by reference.

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to animals or plants, for example humans.

The term “continuous (or continual) analyte sensing” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to theperiod in which monitoring of analyte concentration is continuously,continually, and or intermittently (regularly or irregularly) performed,for example, about every 5 to 10 minutes.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a surface where anelectrochemical reaction takes place. For example, a working electrodemeasures hydrogen peroxide produced by the enzyme-catalyzed reaction ofthe analyte detected, which reacts to create an electric current.Glucose analyte can be detected utilizing glucose oxidase, whichproduces H₂O₂ as a byproduct. H₂O₂ reacts with the surface of theworking electrode, producing two protons (2H⁺), two electrons (2e⁻) andone molecule of oxygen (O₂), which produces the electronic current beingdetected.

The terms “electronic connection,” “electrical connection,” “electricalcontact” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), and referwithout limitation to any connection between two electrical conductorsknown to those in the art. In one embodiment, electrodes are inelectrical connection with the electronic circuitry of a device.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. Thesensing region generally comprises a non-conductive body, a workingelectrode (anode), and can include a reference electrode (optional),and/or a counter electrode (cathode) forming electrochemically reactivesurfaces on the body.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a region of the membrane system that can bea layer, a uniform or non-uniform gradient (for example, an anisotropicregion of a membrane), or a portion of a membrane.

The term “distal to” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the spatial relationship between variouselements in comparison to a particular point of reference. In general,the term indicates an element is located relatively far from thereference point than another element.

The term “proximal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively near to the reference point than another element.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted for insertion into and/or existence within aliving body of a host.

The term “ex vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted to remain and/or exist outside of a livingbody of a host.

The terms “raw data,” “raw data stream”, “raw data signal”, “datasignal”, and “data stream” as used herein are broad terms, and are to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refer without limitation to an analog or digital signalfrom the analyte sensor directly related to the measured analyte. Forexample, the raw data stream is digital data in “counts” converted by anA/D converter from an analog signal (for example, voltage or amps)representative of an analyte concentration. The terms can include aplurality of time spaced data points from a substantially continuousanalyte sensor, each of which comprises individual measurements taken attime intervals ranging from fractions of a second up to, for example, 1,2, or 5 minutes or longer. In some embodiments, the terms can refer todata that has been integrated or averaged over a time period (e.g., 5minutes).

The term “count” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.For example, a raw data stream or raw data signal measured in counts isdirectly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode. In some embodiments, the terms can refer to data that hasbeen integrated or averaged over a time period (e.g., 5 minutes).

The terms “sensor” and “sensor system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a device,component, or region of a device by which an analyte can be quantified.

The term “needle” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a slender hollow instrument for introducingmaterial into or removing material from the body.

The terms “operatively connected,” “operatively linked,” “operablyconnected,” and “operably linked” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to one or morecomponents linked to one or more other components. The terms can referto a mechanical connection, an electrical connection, or any connectionthat allows transmission of signals between the components. For example,one or more electrodes can be used to detect the amount of analyte in asample and to convert that information into a signal; the signal canthen be transmitted to a circuit. In such an example, the electrode is“operably linked” to the electronic circuitry. The terms include wiredand wireless connections.

The terms “membrane” and “membrane system” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to apermeable or semi-permeable membrane that can be comprised of one ormore domains and is typically constructed of materials of one or moremicrons in thickness, which is permeable to oxygen and to an analyte,e.g., glucose or another analyte. In one example, the membrane systemcomprises an immobilized glucose oxidase enzyme, which enables areaction to occur between glucose and oxygen whereby a concentration ofglucose can be measured.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to acomputer system, state machine, processor, and the like designed toperform arithmetic or logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the relationship and/orprocess of determining the relationship between the sensor data and thecorresponding reference data, which can be used to convert sensor datainto values substantially equivalent to the reference data. In someembodiments, namely, in continuous analyte sensors, calibration can beupdated or recalibrated over time if changes in the relationship betweenthe sensor data and reference data occur, for example, due to changes insensitivity, baseline, transport, metabolism, and the like.

The terms “interferents” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to effectsand/or species that interfere with the measurement of an analyte ofinterest in a sensor to produce a signal that does not accuratelyrepresent the analyte concentration. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that substantially overlaps that of the analyte tobe measured, thereby producing a false positive signal.

The term “single point glucose monitor” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a device that canbe used to measure a glucose concentration within a host at a singlepoint in time, for example, some embodiments utilize a small volume invitro glucose monitor that includes an enzyme membrane such as describedwith reference to U.S. Pat. No. 4,994,167 and U.S. Pat. No. 4,757,022.It should be understood that single point glucose monitors can measuremultiple samples (for example, blood, or interstitial fluid); howeveronly one sample is measured at a time and typically requires some userinitiation and/or interaction.

The term “specific gravity” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the ratio of density of amaterial (e.g., a liquid or a solid) to the density of distilled water.

The terms “substantial” and “substantially” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount that provides a desired function. For example, anamount greater than 50 percent, an amount greater than 60 percent, anamount greater than 70 percent, an amount greater than 80 percent, or anamount greater than 90 percent.

The term “casting” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a process where a fluid material is appliedto a surface or surfaces and allowed to cure or dry. The term is broadenough to encompass a variety of coating techniques, for example, usinga draw-down machine (i.e., drawing-down), dip coating, spray coating,spin coating, and the like.

The term “dip coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesdipping an object or material into a liquid coating substance.

The term “spray coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesspraying a liquid coating substance onto an object or material.

The term “spin coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a coating process in which athin film is created by dropping a raw material solution onto asubstrate while it is rotating.

The terms “solvent” and “solvent system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to substances (e.g.,liquids) capable of dissolving or dispersing one or more othersubstances. Solvents and solvent systems can include compounds and/orsolutions that include components in addition to the solvent itself.

The term “baseline,” “noise” and “background signal” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to acomponent of an analyte sensor signal that is not related to the analyteconcentration. In one example of a glucose sensor, the baseline iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation potentialthat overlaps with hydrogen peroxide). In some embodiments wherein acalibration is defined by solving for the equation y=m×+b, the value ofb represents the baseline, or background, of the signal.

The terms “sensitivity” and “slope” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to an amount ofelectrical current produced by a predetermined amount (unit) of themeasured analyte. For example, in one preferred embodiment, a glucosesensor has a sensitivity (or slope) of from about 1 to about 25 picoAmpsof current for every 1 mg/dL of glucose.

The terms “baseline and/or sensitivity shift,” “baseline and/orsensitivity drift,” “shift,” and “drift” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a change in thebaseline and/or sensitivity of the sensor signal over time. While theterm “shift” generally refers to a substantially distinct change over arelatively short time period, and the term “drift” generally refers to asubstantially gradual change over a relatively longer time period, theterms can be used interchangeably and can also be generally referred toas “change” in baseline and/or sensitivity.

The term “hypoglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which alimited or low amount of glucose exists in a host. Hypoglycemia canproduce a variety of symptoms and effects but the principal problemsarise from an inadequate supply of glucose as fuel to the brain,resulting in impairment of function (neuroglycopemia). Derangements offunction can range from vaguely “feeling bad” to coma, and (rarely)permanent brain damage or death.

The term “hyperglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which anexcessive or high amount of glucose exists in a host. Hyperglycemia isone of the classic symptoms of diabetes mellitus. Non-diabetichyperglycemia is associated with obesity and certain eating disorders,such as bulimia nervosa. Hyperglycemia is also associated with otherdiseases (or medications) affecting pancreatic function, such aspancreatic cancer. Hyperglycemia is also associated with poor medicaloutcomes in a variety of clinical settings, such as intensive orcritical care settings.

The term “potentiostat” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an electronic instrument thatcontrols the electrical potential between the working and referenceelectrodes at one or more preset values. Typically, a potentiostat worksto keep the potential constant by noticing changes in the resistance ofthe system and compensating inversely with a change in the current. As aresult, a change to a higher resistance would cause the current todecrease to keep the voltage constant in the system. In someembodiments, a potentiostat forces whatever current is necessary to flowbetween the working and counter electrodes to keep the desiredpotential, as long as the needed cell voltage and current do not exceedthe compliance limits of the potentiostat.

The terms “electronics” and “sensor electronics” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toelectronics operatively coupled to the sensor and configured to measure,process, receive, and/or transmit data associated with a sensor. In someembodiments, the electronics include at least a potentiostat thatprovides a bias to the electrodes and measures a current to provide theraw data signal. The electronics are configured to calculate at leastone analyte sensor data point. For example, the electronics can includea potentiostat, A/D converter, RAM, ROM, and/or transmitter. In someembodiments, the potentiostat converts the raw data (e.g., raw counts)collected from the sensor and converts it to a value familiar to thehost and/or medical personnel. For example, the raw counts from aglucose sensor can be converted to milligrams of glucose per deciliterof blood (e.g., mg/dl). In some embodiments, the sensor electronicsinclude a transmitter that transmits the signals from the potentiostatto a receiver (e.g., a remote analyzer, such as but not limited to aremote analyzer unit), where additional data analysis and glucoseconcentration determination can occur.

The terms “coupling” and “operatively coupling” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to ajoining or linking together of two or more things, such as two parts ofa device or two devices, such that the things can function together. Inone example, two containers can be operatively coupled by tubing, suchthat fluid can flow from one container to another. Coupling does notimply a physical connection. For example, a transmitter and a receivercan be operatively coupled by radio frequency (RF)transmission/communication.

The term “fluid communication” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to two or more components (e.g.,things such as parts of a body or parts of a device) functionally linkedsuch that fluid can move from one component to another. These terms donot imply directionality.

The terms “continuous” and “continuously” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to thecondition of being marked by substantially uninterrupted extension inspace, time or sequence. In one embodiment, an analyte concentration ismeasured continuously or continually, for example at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer. It should be understood that continuous glucosesensors generally continually measure glucose concentration withoutrequired user initiation and/or interaction for each measurement, suchas described with reference to U.S. Pat. No. 6,001,067, for example.These terms include situations wherein data gaps can exist (e.g., when acontinuous glucose sensor is temporarily not providing data).

The term “medical device” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument, apparatus,implement, machine, contrivance, implant, in vitro reagent, or othersimilar or related article, including a component part, or accessorywhich is intended for use in the diagnosis of disease or otherconditions, or in the cure, mitigation, treatment, or prevention ofdisease, in man or other animals, or intended to affect the structure orany function of the body of man or other animals. Medical devices thatcan be used in conjunction with various embodiments of the analytesensor system include any monitoring device requiring placement in ahuman vessel, duct or body cavity, a dialysis machine, a heart-lungbypass machine, blood collection equipment, a blood pressure monitor, anautomated blood chemistry analysis device and the like.

The term “blood pressure monitor” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument for monitoringthe blood pressure of a human or other animal. For example, a bloodpressure monitor can be an invasive blood pressure monitor, whichperiodically monitors the host's blood pressure via a peripheral artery,using a blood pressure transducer, such as but not limited to adisposable blood pressure transducer. Utah Medical Products Inc.(Midvale, Utah, USA) produces a variety of Deltran® Brand disposableblood pressure transducers that are suitable for use with variousembodiments disclosed herein.

The term “pressure transducer” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a component of anintra-arterial blood pressure monitor that measures the host's bloodpressure.

The term “blood chemistry analysis device” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refers without limitation to a device thatmeasures a variety of blood components, characteristics or analytestherein. In one embodiment, a blood chemistry analysis deviceperiodically withdraws an aliquot of blood from the host, measuresglucose, O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea,bilirubin, creatinine, hematocrit, various minerals, and/or variousmetabolites, and the like, and returns the blood to the host'scirculatory system. A variety of devices exist for testing various bloodproperties/analytes at the bedside, such as but not limited to the bloodgas and chemistry devices manufactured by Via Medical (Austin, Tex.,USA).

The term “vascular access device” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to any device that is incommunication with the vascular system of a host. Vascular accessdevices include but are not limited to catheters, shunts, bloodwithdrawal devices and the like.

The term “catheter” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to a tube that can be inserted into a host'sbody (e.g., cavity, duct or vessel). In some circumstances, cathetersallow drainage or injection of fluids or access by medical instrumentsor devices. In some embodiments, a catheter is a thin, flexible tube(e.g., a “soft” catheter). In alternative embodiments, the catheter canbe a larger, solid tube (e.g., a “hard” catheter). The term “cannula” isinterchangeable with the term “catheter” herein.

The term “indwell” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to reside within a host's body. Some medicaldevices can indwell within a host's body for various lengths of time,depending upon the purpose of the medical device, such as but notlimited to a few hours, days, weeks, to months, years, or even thehost's entire lifetime. In one exemplary embodiment, an arterialcatheter may indwell within the host's artery for a few hours, days, aweek, or longer, such as but not limited to the host's perioperativeperiod (e.g., from the time the host is admitted to the hospital to thetime he is discharged).

The term “sheath” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a covering or supporting structure thatfits closely around something, for example, in the way that a sheathcovers a blade. In one exemplary embodiment, a sheath is a slender,flexible, polymer tube that covers and supports a wire-type sensor priorto and during insertion of the sensor into a catheter.

The term “slot” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a relatively narrow opening.

The term “regulator” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to a device that regulates the flow of a fluidor gas. For example, a regulator can be a valve or a pump.

The term “pump” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a device used to move liquids, or slurries.In general, a pump moves liquids from lower pressure to higher pressure,and overcomes this difference in pressure by adding energy to the system(such as a water system).

The term “valve” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a device that regulates the flow ofsubstances (either gases, fluidized solids, slurries, or liquids), forexample, by opening, closing, or partially obstructing a passagewaythrough which the substance flows. In general, a valve allows no flow,free flow and/or metered flow through movement of the valve between oneor more discreet positions.

The term “retrograde” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to orientation (e.g., of a catheter) againstthe direction of blood flow.

The term “antegrade” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to orientation (e.g., of a catheter) with thedirection of blood flow.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to any biological material to betested for the presence and/or concentration of an analyte in a sample.Examples biological samples that may be tested include blood, serum,plasma, saliva, urine, ocular fluid, semen, and spinal fluid, tissue,and the like.

The terms “small diameter sensor,” “small structured sensor,” and“micro-sensor” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to sensing mechanisms that are less than about2 mm in at least one dimension, and more preferably less than about 1 mmin at least one dimension. In some embodiments, the sensing mechanism(sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6,0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some embodiments, the sensingmechanism is a needle-type sensor, wherein the diameter is less thanabout 1 mm (see, for example, U.S. Pat. No. 6,613,379 to Ward et al. andin U.S. Patent Publication No. US-2006-0020187-A1, both of which areincorporated herein by reference in their entirety). In some alternativeembodiments, the sensing mechanism includes electrodes deposited on aplanar substrate, wherein the thickness of the implantable portion isless than about 1 mm, see, for example U.S. Pat. No. 6,175,752 to Say etal. and U.S. Pat. No. 5,779,665 to Mastrototaro et al., both of whichare incorporated herein by reference in their entirety.

Overview

Intensive care medicine or critical care medicine is concerned withproviding greater than ordinary medical care and/or observation topeople in a critical or unstable condition. In recent years, anincreasingly urgent need has arisen, for more intensive care medicine.People requiring intensive care include those recovering after majorsurgery, with severe head trauma, life-threatening acute illness,respiratory insufficiency, coma, haemodynamic insufficiency, severefluid imbalance or with the failure of one or more of the major organsystems (life-critical systems or others). More than 5 million peopleare admitted annually to intensive care units (ICUs) and critical careunits (CCUs) in the United States.

Intensive care is generally the most expensive, high technology andresource intensive area of medical care. In the United States estimatesof the year 2000 expenditure for critical care medicine ranged from$15-55 billion accounting for about 0.5% of GDP and about 13% ofnational health care expenditure. As the U.S. population ages, thesecosts will increase substantially. Accordingly, there is an urgent needto reducing costs while at the same time reducing ICU/CCU mortalityrates by improving care. Some embodiments disclosed herein are suitablefor use in an intensive care or critical care unit of a medical carefacility for substantially continuously measuring a host's analyteconcentration.

Hyperglycemia is a medical condition in which an excessive amount ofglucose circulates in a host. Medical studies suggest a relationshipbetween hyperglycemia and host outcome in intensive/critical caresettings. For example, perioperative hyperglycemia is associated withincreased rates and severity of myocardial infarction (MI) and stroke,while tight glucose control with intravenous (IV) insulin therapy islinked to a 30% reduction in mortality one year after admission foracute MI. Furthermore, strict in-hospital glucose control is associatedwith 40% reductions of morbidity, mortality, sepsis, dialysis, bloodtransfusions, as well as reduced length of stay, reduced costs and thelike.

Hyperglycemia can also be an issue in non-critical care settings, suchas in the general hospital population, such as for diabetes hostsadmitted for non-glucose-related medical conditions, or in clinicalsettings, such as the doctor's office, such as during glucose challengetests, or treatment of the elderly or the very young, or others who mayhave difficulty with glucose control.

Unfortunately, using generally available technology, tight glucosecontrol requires frequent monitoring of the host by the clinical staff,IV insulin or injections, and on-time feeding. Frequent monitoringtypically requires a nurse or other staff member to measure the host'sglucose concentration using a lancet (to obtain a blood sample) and ahand held glucose monitor. The nurse can perform this task many times aday (e.g., every hour or more frequently). This task becomes an undueburden that takes the nurse away from his/her other duties, or requiresextra staff. The preferred embodiments disclose systems and methods toreduce and/or minimize the interaction required to regularly (e.g.,continuously) measure the host's glucose concentration.

Unfortunately it has been shown that an effort to maintain tight controlof glucose levels (e.g., about 80-129 mg/dl) can increase the risk ofhypoglycemia using conventional systems and methods. For example,administration of insulin, quality, and timing of meal ingestion, andthe like can lead to hypoglycemia. Because hypoglycemia can cause shockand death (immediate problems), the clinical staff rigorously avoids it,often by maintaining the host at elevated blood glucose concentrations(which can degrade the clinical outcome in the long run) and causes theproblems of hyperglycemia discussed above.

Accordingly, in spite of clinically demonstrated improvements associatedwith tight glucose control, institutions are slow to adopt the therapydue to the increased workload on the staff as well as a pervasive fearof hypoglycemia, which is potentially life ending. Therefore, there isan urgent need for devices and methods that offer continuous, robustglucose monitoring, to improve patient care and lower medical costs. Thepreferred embodiments describe systems and methods for providingcontinuous glucose monitoring while providing alarms or alerts that aidin avoiding hypoglycemic events.

Hyperglycemia can be managed in a variety of ways. Currently, for hostsin an intensive care setting, such as and ICU, CCU or emergency room(ER), hyperglycemia is managed with sliding-scale IV insulin, that stopsinsulin delivery at about 150 to 200 mg/dl. This generally requiresmonitoring by a nurse (using a hand-held clinical glucose meter) andinsulin administration at least every six hours. Maintaining tightglucose control within the normal range (e.g., 80-110 mg/dl) currentlyrequires hourly or even more frequent monitoring and insulinadministration. This places an undue burden on the nursing staff. Thepreferred embodiments provide devices and methods for automated,continuous glucose monitoring (e.g., indwelling in the circulatorysystem), to enable tight glucose control.

The in vivo continuous analyte monitoring system of the preferredembodiments can be used in clinical settings, such as in the hospital,the doctor's office, long-term nursing facilities, or even in the home.The present device can be used in any setting in which frequent orcontinuous analyte monitoring is desirable. For example, in the ICU,hosts are often recovering from serious illness, disease, or surgery,and control of host glucose levels is important for host recovery. Useof a continuous glucose sensor as described in the preferred embodimentsallows tight control of host glucose concentration and improved hostcare, while reducing hypoglycemic episodes and reducing the ICU staffwork load. For example, the system can be used for the entire hospitalstay or for only a part of the hospital stay.

In another example, the continuous glucose monitor of the preferredembodiments can be used in an ER setting. In the ER, a host may beunable to communicate with the staff. Routine use of a continuousanalyte monitor (e.g., glucose, creatinine, phosphate, electrolytes, ordrugs) can enable the ER staff to monitor and respond to analyteconcentration changes indicative of the host's condition (e.g., thehost's glucose concentration) without host input.

In yet another example, a continuous analyte monitor can be used in thegeneral hospital population to monitor host analyte concentrations, forvarious lengths of time, such as during the entire hospital stay or fora portion of the hospital stay (e.g., only during surgery). For example,a diabetic host's glucose concentration can be monitored during hisentire stay. In another example, a cardiac host's glucose can bemonitored during surgery and while in the ICU, but not after being movedto the general host population. In another example, a jaundiced newborninfant can have his bilirubin concentration continuously monitored by anin-dwelling continuous analyte monitor until the condition has receded.

In addition to use in the circulatory system, the analyte sensor of thepreferred embodiments can be used in other body locations. In someembodiments, the sensor is used subcutaneously. In another embodiment,the sensor can be used intracranially. In another embodiment, the sensorcan be used within the spinal compartment, such as but not limited tothe epidural space. In some embodiments, the sensor of the preferredembodiments can be used with or without a catheter.

Applications/Uses

One aspect of the preferred embodiments provides a system for in vivocontinuous analyte monitoring (e.g., glucose, O₂, CO₂, PCO₂, PO₂,potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit,various minerals, various metabolites, and the like) that can beoperatively coupled to a catheter to measure analyte concentrationwithin the host's blood stream. In some embodiments, the system includesan analyte sensor that extends a short distance into the blood stream(e.g., out of the catheter) without substantially occluding the catheteror the host's blood stream. The catheter can be fluidly coupled toadditional IV and diagnostic devices, such as a saline bag, an automatedblood pressure monitor, or a blood chemistry monitor device. In someembodiments, blood samples can be removed from the host via the sensorsystem, as described elsewhere herein. In one embodiment, the sensor isa glucose sensor, and the medical staff monitors the host's glucoselevel.

FIGS. 1A to 1E illustrate one embodiment of an exemplary analyte sensorsystem 10 for measuring an analyte (e.g., glucose, urea, potassium, pH,proteins, etc.) that includes a catheter 12 configured to be inserted orpre-inserted into a host's blood stream. In clinical settings, cathetersare often inserted into hosts to allow direct access to the circulatorysystem without frequent needle insertion (e.g., venipuncture). Suitablecatheters can be sized as is known and appreciated by one skilled in theart, such as but not limited to from about 1 French (0.33 mm) or less toabout 30 French (10 mm) or more; and can be, for example, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 Frenchis equivalent to about 1 mm) and/or from about 33 gauge or less to about16 gauge or more, for example, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24,23, 22, 21, 20, 19, 18, 17, or 16 gauge. Additionally, the catheter canbe shorter or longer, for example 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 inchesin length or longer. The catheter can be manufactured of any medicalgrade material known in the art, such as but not limited to polymers andglass as described herein. A catheter can include a single lumen ormultiple lumens. A catheter can include one or more perforations, toallow the passage of host fluid through the lumen of the catheter.

The terms “inserted” or “pre-inserted” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to insertion of onething into another thing. For example, a catheter can be inserted into ahost's blood stream. In some embodiments, a catheter is “pre-inserted,”meaning inserted before another action is taken (e.g., insertion of acatheter into a host's blood stream prior to insertion of a sensor intothe catheter). In some exemplary embodiments, a sensor is coupled to apre-inserted catheter, namely, one that has been previously inserted (orpre-inserted) into the host's circulatory system.

Referring now to FIGS. 1A to 1E, in some embodiments, the catheter 12 isa thin, flexible tube having a lumen 12 a, such as is known in the art.In some embodiments, the catheter can be rigid; in other embodiments,the catheter can be custom manufactured to desired specifications (e.g.,rigidity, dimensions, etc). The catheter can be a single-lumen catheteror a multi-lumen catheter. At the catheter's proximal end is a smallorifice 12 b for fluid connection of the catheter to the blood stream.At the catheter's distal end is a connector 18, such as a leur connectoror other fluid connector known in the art.

The illustrations of FIGS. 1A to 1E show one exemplary embodiment of theconnector 18 including a flange 18 a and a duct 18 b. In the exemplaryembodiment, the flange 18 a is configured to enable connection of thecatheter to other medical equipment (e.g., saline bag, pressuretransducer, blood chemistry device, and the like) or capping (e.g., witha bung and the like). Although one exemplary connector is shown, oneskilled in the art appreciates a variety of standard or custom madeconnectors suitable for use with the preferred embodiments. The duct 18b is in fluid communication with the catheter lumen and terminates in aconnector orifice 18 c.

In some embodiments, the catheter is inserted into the host's bloodstream, such as into a vein or artery by any useful method known in theart. Generally, prior to and during insertion, the catheter is supportedby a hollow needle or trochar (not shown). For example, the supportedcatheter can be inserted into a peripheral vein or artery, such as inthe host's arm, leg, hand, or foot. Typically, the supporting needle isremoved (e.g., pulled out of the connector) and the catheter isconnected (e.g., via the connector 18) to IV tubing and a saline drip,for example. However, in one embodiment, the catheter is configured tooperatively couple to medical equipment, such as but not limited to asensor system of the preferred embodiments. Additionally and/oralternatively, the catheter can be configured to operatively couple toanother medical device, such as a pressure transducer, for measurementof the host's blood pressure.

In some embodiments, the catheter and the analyte sensor are configuredto indwell within the host's blood stream in vivo. An indwelling medicaldevice, such as a catheter or implant, is disposed within a portion ofthe body for a period of time, from a few minutes or hours to a fewdays, months, or even years. An indwelling catheter is typicallyinserted within a host's vein or artery for a period of time, often 2 ormore days, a month, or even a few months. In some embodiments, thecatheter can indwell in a host's artery or vein for the length of aperioperative period (e.g., the entire hospital stay) or for shorter orlonger periods. In some embodiments, the use of an indwelling catheterpermits continuous access of an analyte sensor to a blood stream whilesimultaneously allowing continuous access to the host's blood stream forother purposes, for example, the administration of therapeutics (e.g.,fluids, drugs, etc.), measurement of physiologic properties (e.g., bloodpressure), fluid removal, and the like.

Referring again to FIGS. 1A to 1E, the system 10 also includes ananalyte sensor 14 configured to extend through the catheter lumen 12 a(see FIG. 1E), out of the catheter orifice 12 b and into the host'sblood stream by about 0.010 inches to about 1 inch, or shorter or longerlengths. In some embodiments, however, the sensor may not extend out ofthe catheter, for example, can reside just inside the catheter tip. Thesensor can extend through the catheter in any functional manner. In someembodiments, the sensor is configured to be held on an inner surface(e.g., the lumen) or outer surface of the catheter, while in otherembodiments, the sensor is configured to “free float” within the lumenof the catheter.

In some embodiments, the sensor 14 is configured to measure theconcentration of an analyte (e.g., glucose, O₂, CO₂, PCO₂, PO₂,potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit,various minerals, various metabolites, and the like) within the host'sblood stream. Preferably, the sensor includes at least one electrode(see, e.g., FIG. 3B), for example a working electrode; however anycombination of working electrode(s), reference electrode(s), and/orcounter electrode(s) can be implemented as is appreciated by one skilledin the art. Preferably, the sensor 14 includes at least one exposedelectroactive area (e.g., working electrode), a membrane system (e.g.,including an enzyme), a reference electrode (proximal to or remote fromthe working electrode), and an insulator material. Various systems andmethods for design and manufacture of continuous analyte sensors aredescribed in more detail elsewhere herein. In some embodiments, thesensor is a needle-type continuous analyte sensor, configured asdisclosed in U.S. Patent Publication No. US-2006-0020192-A1 and U.S.Patent Publication No. US-2006-0036143, both of which are incorporatedherein by reference in their entirety. In some embodiments, the sensoris configured to measure glucose concentration. Exemplary sensorconfigurations are discussed in more detail, elsewhere herein.

Referring to FIGS. 1A to 1E, the sensor has a proximal end 14 a and adistal end 14 b. At its distal end 14 b, the sensor 14 is associatedwith (e.g., connected to, held by, extends through, and the like) afluid coupler 20 having first and second sides (20 a and 20 b,respectively). The fluid coupler is configured to mate (via its firstside 20 a) to the catheter connector 18. In one embodiment, a skirt 20 cis located at the fluid coupler's first side and includes an interiorsurface 20 d with threads 20 e (see FIGS. 1D and 1E). In thisembodiment, the fluid coupler is configured to mate with the connectorflange 18 a, which is screwed into the fluid coupler via the screwthreads. However, in other embodiments, the fluid coupler is configuredto mate with the connector using any known mating configuration, forexample, a snap-fit, a press-fit, an interference-fit, and the like, andcan include a locking mechanism to prevent separation of the connectorand fluid coupler. The fluid coupler 20 includes a lumen 20 f extendingfrom a first orifice 20 h on its first side 20 a to a second orifice 20i located on the fluid coupler's second side 20 b (FIGS. 1C1 to 1E).When the catheter connector is mated with the fluid coupler, thecatheter's lumen 12 a is in fluid communication with the fluid coupler'slumen 20 f via orifices 18 c and 20 h.

FIGS. 1A to 1D show one embodiment of a fluid coupler 20, namely, aY-coupler; however, any known coupler configuration can be used,including but not limited to a straight coupler, a T-coupler, across-coupler, a custom configured coupler, and the like. In someembodiments, the fluid coupler includes at least one valve (e.g., aseptum, a 3-way valve, a stop-cock valve), which can be used for avariety of purposes (e.g., injection of drugs). The fluid coupler can bemade of any convenient material, such as but not limited to plastic,glass, metal or combinations thereof and can be configured to withstandknown sterilization techniques.

In the exemplary embodiment, the second side 20 b of the fluid coupler20 is configured to be operably connected to IV equipment, anothermedical device or to be capped, and can use any known matingconfiguration, for example, a snap-fit, a press-fit, aninterference-fit, and the like. In one exemplary embodiment, the secondside 20 b is configured to mate with a saline drip, for delivery ofsaline to the host. For example, the saline flows from an elevated bagof sterile saline via tubing, through the fluid coupler, through thecatheter and into the host's blood system (e.g., vein or artery). Inanother embodiment, a syringe can be mated to the fluid coupler, forexample, to withdraw blood from the host, via the catheter. Additionalconnection devices (e.g., a three-way valve) can be operably connectedto the fluid coupler, to support additional functionality and connectionof various devices, such as but not limited to a blood pressuretransducer.

Referring to the exemplary embodiment of FIGS. 1A and 1E, at least aportion of the sensor 14 passes through the fluid coupler 20 (e.g., thefluid coupler lumen 20 f) and is operatively connected to sensorelectronics (not shown) via a hardwire 24. In alternative embodimentshowever, the sensor electronics can be disposed in part or in whole withthe fluid coupler (e.g., integrally with or proximal to) or can bedisposed in part or in whole remotely from the fluid coupler (e.g., on astand or at the bed side). Connections between the sensor and sensorelectronics (in part or in whole) can be accomplished using known wiredor wireless technology. In one exemplary embodiment, the sensor ishardwired to the electronics located substantially wholly remote fromthe fluid coupler (e.g., disposed on a stand or near the bedside); oneadvantage of remote electronics includes enabling a smaller sized fluidcoupler design. In another exemplary embodiment, a portion of the sensorelectronics, such as a potentiostat, is disposed on the fluid couplerand the remaining electronics (e.g., electronics for receiving, dataprocessing, printing, connection to a nurses' station, etc.) aredisposed remotely from the fluid coupler (e.g., on a stand or near thebedside). One advantage of this design can include more reliableelectrical connection with the sensor in some circumstances. In thisembodiment, the potentiostat can be hardwired directly to the remainingelectronics or a transmitter can be disposed on or proximal to the fluidcoupler, for remotely connecting the potentiostat to the remainingelectronics (e.g., by radio frequency (RF)). In another exemplaryembodiment, all of the sensor electronics can be disposed on the fluidcoupler. In still another embodiment, the sensor electronics disposed onthe fluid coupler include a potentiostat.

Referring again to FIGS. 1A to 1E, a protective sheath 26 is configuredto cover at least a portion of the sensor 14 during insertion, andincludes hub 28 and slot 30. In general, the protective sheath protectsand supports the sensor prior to and during insertion into the catheter12 via the connector 18. The protective sheath can be made ofbiocompatible polymers known in the art, such as but not limited topolyethylene (PE), polyurethane (PE), polyvinyl chloride (PVC),polycarbonate (PC), nylon, polyamides, polyimide,polytetrafluoroethylene (PTFE), Teflon, nylon and the like. Theprotective sheath includes a hub 28, for grasping the sheath (e.g.,while maintaining sterilization of the sheath). In this embodiment, thehub additionally provides for mating with the second side 20 b of thefluid coupler 20, prior to and during sensor insertion into thecatheter. In this exemplary embodiment, the slot of the protectivesheath is configured to facilitate release of the sensor therefrom. Inthis embodiment, after the sensor has been inserted into the catheter,the hub is grasped and pulled from the second side of the fluid coupler.This action peels the protective sheath from the sensor (e.g., thesensor slides through the slot as the sheath is removed), leaving thesensor within the catheter. The second side of the fluid coupler can beconnected to other medical devices (e.g., a blood pressure monitor) oran IV drip (e.g., a saline drip), or capped. In alternative embodiments,the sheath can fold (e.g., fold back or concertinas) or retract (e.g.,telescope) during insertion, to expose the sensor. In other embodiments,the sheath can be configured to tear away from the sensor before,during, or after insertion of the sensor. In still other embodiments,the sheath can include an outlet hole 30 a, to allow protrusion of thesensor from the back end of the sheath (e.g., near the hub 28). Oneskilled in the art will recognize that additional configurations can beused, to separate the sensor 14 from the sheath 26.

In some embodiments, the sheath 26 can be optional, depending upon thesensor design. For example, the sensor can be inserted into a catheteror other vascular access device with or without the use of a protectivesheath). In some embodiments, the sensor can be disposed on the outersurface of a catheter (as described elsewhere herein) or on the innersurface of a catheter; and no sheath is provided. In other embodiments,a multi-lumen catheter can be provided with a sensor already disposedwithin one of the lumens; wherein the catheter is inserted into thehost's vein or artery with the sensor already disposed in one of thelumens.

In some alternative embodiments, an analyte sensor is integrally formedon a catheter. In various embodiments, the catheter can be placed into ahost's vein or artery in the usual way a catheter is inserted, as isknown by one skilled in the art, and the host's analyte concentrationmeasured substantially continuously. In some embodiments, the sensorsystem can be coupled to one or more additional devices, such as asaline bag, an automated blood pressure monitor, a blood chemistrymonitor device, and the like. In one exemplary embodiment, theintegrally formed analyte sensor is a glucose sensor.

FIGS. 2A to 2B illustrate one exemplary embodiment of an analyte sensorintegrally formed on a catheter. The system 210 is configured to measurean analyte (e.g., glucose, O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH,lactate, urea, bilirubin, creatinine, hematocrit, various minerals,various metabolites, and the like) and generally includes a catheter 212configured for insertion into a host's blood stream (e.g., via a vein orartery) and a sensor at least partially integrally formed on thecatheter's exterior surface 232. Preferably, the sensor 214 includes atleast one exposed electroactive area 240 (e.g., a working electrode), amembrane system (e.g., including an enzyme), a reference electrode(proximal to or remote from the working electrode), and an insulator.Various systems and methods for design and manufacture of continuousanalyte sensors are described in more detail elsewhere herein.

In this embodiment, the catheter includes a lumen 212 a and an orifice212 b at its proximal end, for providing fluid connection from thecatheter's lumen to the host's blood stream (see FIG. 2A).

In some embodiments, the catheter is inserted into a vein, as describedelsewhere herein. In other embodiments, the catheter is inserted into anartery, as described elsewhere herein. The catheter can be any type ofvenous or arterial catheter commonly used in the art (e.g., peripheralcatheter, central catheter, Swan-Gantz catheter, etc.). The catheter canbe made of any useful medical grade material (e.g., polymers and/orglass) and can be of any size, such as but not limited to from about 1French (0.33 mm) or less to about 30 French (10 mm) or more; forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 20 French (3 French is equivalent to about 1 mm). In certainembodiments, the catheter can be a single lumen catheter or amulti-lumen catheter. In some embodiments, the catheter can include oneor more perforations, to allow the passage of host fluid through thelumen of the catheter.

At its distal end 212 c, the catheter 212 includes (e.g., in fluidcommunication) a connector 218. The connector can be of any known type,such as a leur lock, a T-connector, a Y-connector, a cross-connector ora custom configuration, for example. In some embodiments, the connectorincludes at least one valve. At a second side 218 e (e.g., back end),the connector 218 can be operatively connected to a saline system (e.g.,saline bag and tubing), other medical devices (e.g., automatic bloodchemistry machine, dialysis machine, a blood bag for collecting donatedblood, etc.), or capped.

In some embodiments, the system 210 includes sensor electronics (notshown) operatively connected to the analyte sensor, wherein the sensorelectronics are generally configured to measure and/or process thesensor data as described in more detail elsewhere herein. In someembodiments, the sensor electronics can be partially or wholly disposedwith (e.g., integral with, disposed on, or proximal to) the connector218 at the distal end of the catheter or partially or wholly remote fromthe catheter (e.g., on a stand or on the bedside). In one embodiment,the sensor electronics disposed with the connector include apotentiostat. In some embodiments, the sensor electronics are configuredto measure the host's analyte concentration substantially continuously.For example, the sensor can measure the analyte concentrationcontinuously or at time intervals ranging from fractions of a second upto, for example, 1, 2, or 5 minutes or longer.

FIGS. 2C to 2F illustrate additional embodiments of the sensor shown inFIGS. 2A to 2B. The catheter 212 is shown with an integral sensor 214having at least one electrode 240 formed on its exterior surface 232(e.g., FIG. 2F). In general, the sensor can be designed with 1, 2, 3, 4or more electrodes and can be connected by traces (or the like) toelectrical contacts 218 d (or the like) at the second end of theconnector 218 (e.g., FIGS. 2A to 2F). In some embodiments, the sensor ishard-wired to the sensor electronics; alternatively, any operableconnection can be used. Preferably, the sensor includes at least oneworking electrode and at least one reference or counter electrode. Insome embodiments, the reference electrode is located proximal to the atleast one working electrode (e.g., adjacent to or near to the workingelectrode). In some alternative embodiments, the reference electrode islocated remotely from the working electrode (e.g., away from the workingelectrode, such as but not limited to within the lumen of the catheter212 (or connector 218), on the exterior of the sensor system, in contactwith the patient (e.g., on the skin), or the like). In some embodiments,the reference electrode is located proximal to or within the fluidconnector, such as but not limited to, coiled about the catheteradjacent to the fluid connector or coiled within the fluid connector andin contact with fluid flowing through the fluid coupler, such as salineor blood. In some embodiments, the sensor can also include one or moreadditional working electrodes (e.g., for measuring baseline, formeasuring a second analyte, or for measuring a substantially non-analyterelated signal, and the like, such as described in more detail in U.S.Patent Publication No. US-2005-0143635-A1 and U.S. Patent PublicationNo. US-2007-0027385-A1 which are incorporated herein by reference intheir entirety. In some embodiments one or more counter electrodes canbe provided on a surface of the catheter or within or on the fluidconnector.

In some of the preferred embodiments, the catheter is designed toindwell within a host's blood flow (e.g., a peripheral vein or artery)and remain in the blood flow for a period of time (e.g., the catheter isnot immediately removed). In some embodiments, the indwelling cathetercan be inserted into the blood flow for example, for a few minutes ormore, or from about 1 to 24 hours, or from about 1 to 10 days, or evenlonger. For example, the catheter can indwell in the host's blood streamduring an entire perioperative period (e.g., from host admittance,through an operation, and to release from the hospital).

In some embodiments, the catheter is configured as an intravenouscatheter (e.g., configured to be inserted into a vein). The catheter canbe inserted into any commonly used vein, such as in a peripheral vein(e.g., one of the metacarpal veins of the arm); in some embodiments(e.g., such as described with reference to FIGS. 1A to 1E) the analytesensor inserted into a catheter. In alternative embodiments, the sensoris integrally formed on a catheter such as described in more detail withreference to FIGS. 2A to 2F, for example. Other veins, such as leg orfoot veins, hand veins, or even scalp or umbilical veins, can also beused.

In addition to sensing analyte levels via a sensor system as describedherein, the intravenous catheter can be used for delivery of fluidsand/or drugs to the host's circulatory system. The catheter can beconfigured to be coupled to other medical devices or functions, forexample, saline, blood products, total parenteral feeding or medicationscan be given to the host via the indwelling intravenous catheter. Insome embodiments, the catheter can be operatively connected to a pump,such as an infusion pump, to facilitate flow of the fluids into the hostand a desired rate. For example, an infusion pump can pump saline intothe host at a rate of Icc per minute, or at higher or lower rates. Therate of infusion can be changed (increased or decreased). For example,an infusion can be temporarily stopped, to permit injection of painmedication into the IV system, followed by increasing the infusion rate(e.g., for 5 minutes) to rapidly deliver the pain medication to thehost's circulatory system.

In some embodiments, the catheter is configured as an arterial catheter(e.g., configured to be inserted into an arterial line or as part of anarterial line). Typically, an arterial catheter is inserted in the wrist(radial artery), armpit (axillary artery), groin (femoral artery), orfoot (pedal artery). Generally, arterial catheters provide access to thehost's blood stream (arterial side) for removal of blood samples and/orapplication of test devices, such as but not limited to a pressuretransducer (for measuring blood pressure automatically), however,arterial catheters can also be used for delivery of fluids ormedications. In one embodiment, a catheter is inserted into an arterialline and the sensor inserted into the catheter (e.g., functionallycoupled) as described elsewhere herein. Saline filled non-compressibletubing is then coupled to the sensor, followed by a pressure transducer.An automatic flushing system (e.g., saline) is coupled to the tubing aswell as a pressure bag to provide the necessary pressure. Electronicsare generally operatively coupled to the pressure transducer forcalculating and displaying a variety of parameters including bloodpressure. Other medical devices can also be connected to the arterialcatheter, to measure various blood components, such as but not limitedto O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea, bilirubin,creatinine, hematocrit, various minerals, various metabolites, and thelike.

In another embodiment, a blood pressure measurement system is insertedinto the host and can be used as is known in the art. The analyte sensor(e.g., glucose sensor), such as the embodiment shown in FIGS. 1A-1E, isinserted into the pre-inserted (e.g., already in-dwelling) catheterusing the following general methodology. First, the pressure transduceris temporarily disabled by disconnecting from the pre-inserted catheter.A cap (optionally) covers the protective slotted sheath and can beremoved so as to enable the sensor to be grasped at the fluid coupler.The sheath, which is generally more rigid than the sensor but lessflexible than a needle, is then threaded through the pre-insertedcatheter so as to extend beyond the catheter into the blood stream(e.g., by about 0.001 inches to about 1 inches). The sheath is thenremoved by sliding the sensor through a small outlet hole and/or slot inthe sheath. Thus, the sensor remains within the pre-inserted catheterand the fluid coupler, which supports the distal portion of the sensor,is coupled to the catheter itself. Saline filled non-compressible tubingis then coupled to the second side (e.g., back end) of the fluidcoupler. The sensor electronics (whether adjacent to the fluid coupleror otherwise wired to the fluid coupler) are then operatively connected(e.g., wired or wirelessly) to the sensor to initiate sensor function.

In some embodiments, a portion of the sensor system (e.g., sensor,catheter, or other component) can be configured to allow removal ofblood samples from the host's blood stream (e.g., artery or vein).Sample removal can be done using any systems and methods known in theart, for example, as is practiced for removing a blood sample from anarterial catheter (e.g., and arterial line). In one such exemplaryembodiment, any tubing or equipment coupled to the second side of thefluid coupler is disconnected. A syringe is then be coupled to thesecond side and blood removed via the catheter by pulling back on thesyringe plunger. In a further embodiment, saline can be flushed throughthe fluid coupler and catheter. In another embodiment, the fluid couplercan be configured with a side valve, to allow coupling of a syringe, forremoval of blood samples or delivery of fluids, such as medications,without disconnecting attached tubing of equipment, and the like. Instill another embodiment, a valve or diaphragm, for access to the systemby a syringe, can be coupled into the tubing at a short distance fromthe fluid coupler. In yet another embodiment, the sensor is integrallyformed on the arterial catheter, such as the embodiment shown in FIGS.2A-2B, and tubing can be disconnected from the connector, a syringeoperably associated with the connector, and blood removed with thesyringe. After blood collection, the syringe is removed and the tubingreconnected to the connector.

In still another embodiment, the analyte sensor can be functionallycoupled to an extracorporeal blood flow device. A variety of devicesexist for testing various blood properties/analytes at the bedside, suchas but not limited to the blood gas and chemistry devices manufacturedby Via Medical, Austin, Tex., USA. These devices generally withdraw ablood sample from the host, test the blood sample, and then return it tothe host. Such a device can be connected in series to the arterialcatheter, with the sensor in-between, and using systems and methodsknown in the art. In one embodiment, a sensor, such as the embodimentshown in FIGS. 1A-1E, is functionally connected to an in-dwellingarterial catheter, as described herein, and the extracorporeal bloodflow device is connected to the second side of the fluid coupler. In analternative embodiment, the sensor is integrally formed on the arterialcatheter, such as the embodiment shown in FIGS. 2A-2F, and theextracorporeal blood flow device is functionally connected to theconnector 218. Other devices, such as but not limited to dialysismachines, heart-lung bypass machines or blood collection bags, or othervascular access devices, can be functionally coupled to the analytesensor.

The analyte sensor system of the preferred embodiments can be designedwith a variety of alternative configurations. In some embodiments, thesensor is connected to a fluid connection device. The fluid connectiondevice in these embodiments can be any standard fluid connection deviceknown in the art, such as a fluid coupler, or a fluid coupler custommanufactured to preferred specifications. On its first side, the fluidcoupler is configured to couple to an existing catheter or cannula (asdescribed with reference to FIGS. 1A-1E). The catheter (or cannula) istypically inserted into a vascular access device and/or into a hospitalhost during a hospital stay. For example, the catheter can be insertedinto an arterial line (e.g., for removing blood samples or for measuringblood pressure using a pressure transducer) or a venous line (e.g., forintravenous delivery of drugs and other fluids). In general practice,the catheter is inserted into the host's blood vessel, for example, andmaintained there for a period of time during the host's hospital stay,such as part of the stay or during the entire stay (e.g.,perioperatively). In one alternative embodiment, another vascular accessdevice (e.g., other than a catheter) can be used to receive the sensor.In yet another alternative embodiment, the sensor system of thepreferred embodiments can be inserted into a vascular access device(e.g., rather than the vascular system directly). Some examples ofvascular access devices include but are not limited to, catheters,shunts, automated blood withdrawal devices and the like.

In some embodiments, such as the embodiment illustrated in FIGS. 1A to1E, the system 10 is configured such that the sensor is inserted into avascular access device, such as but not limited to a catheter 12 (e.g.,a catheter that has been inserted into the host's blood stream prior tosensor insertion). In general, catheters are small, flexible tubes(e.g., soft catheter) but they can also be larger, rigid tubes.Catheters are inserted into a host's body cavity, vessel, or duct toprovide access for fluid removal or insertion, or for access to medicalequipment. Catheters can also be inserted into extracorporeal devices,such as but not limed to an arterio-venous shunt for the transfer ofblood from an artery to a vein. Some catheters are used to direct accessto the circulatory system (e.g., venous or arterial catheters, SwanGantz catheters) to allow removal of blood samples, the infusion offluids (e.g., saline, medications, blood or total parenteral feeding) oraccess by medical devices (e.g., stents, extracorporeal blood chemistryanalysis devices, invasive blood pressure monitors, etc.).

Preferably, the sensor is designed to include a protective cap, asillustrated in FIGS. 1A-1E. Namely, FIGS. 1A and 1B illustrates thecatheter (the catheter cap having been removed prior to insertion), wellknown to those skilled in the art, which can be inserted into the host'sblood vessel using standard methods. The sensor 14 is configured formeasurement of an analyte (e.g., glucose) in the host's body, and is influid connection within the catheter lumen, which is in fluid connectionwith the fluid coupler 20 of the sensor. The first side 20 a of thefluid coupler 20 of the sensor is designed to couple to the catheter,e.g., by screwing or snapping thereon, and can also couple (on itssecond side 20 b) with other medical devices. One advantage of the fluidcoupler is that it provides for a small amount of bleed back, to preventair bubbles in the host's blood stream.

The exemplary sensor system 10 of FIGS. 1A and 1B further includes aslotted protective sheath 26 that supports and protects the sensorduring sensor insertion, for example, the sheath increases the sensorvisibility (e.g., the sensor is so thin that it can be difficult forsome people to see without the protective sheath) and provides for easeof sliding the sensor into the catheter. The slotted protective sheathis configured to fit within the fluid coupler and houses the sensorduring insertion of the sensor into the catheter (e.g., an indwellingcatheter within the host's blood flow). Preferably, the protectivesheath is substantially more rigid than the sensor and at the same timesubstantially more flexible that a standard syringe needle, howeverother designs are possible. To facilitate removal of the protectivesheath, a slot 30 is provided with an optional outlet hole 30 a, whichis described in more detail with reference to FIG. 1C, and a hub 28. Bygrasping and pulling the hub, the user (e.g., health care professional)can withdraw the protective sheath after coupling the fluid coupler tothe catheter. Prior to insertion of the sensor, a cap is provided, tocover the protective sheath, for example, to keep the sheath and sensorsterile, and to prevent damage to the components during shipping and/orhandling.

In general, the sensor system is configured with a potentiostat and/orsensor electronics that are operatively coupled to the sensor. In someembodiments, a portion of the sensor electronics, such as thepotentiostat, can be disposed directly on the fluid coupler. However,some or all of the sensor electronics (including the potentiostat) canbe disposed remotely from the fluid coupler (e.g., on the bedside or ona stand) and can be functionally coupled (e.g., wired or wireless), asis generally known to those skilled in the art.

FIGS. 1C1 and 1C2 are cross-sectional views (not to scale) of the fluidcoupler, including a protective sheath 26, a sensor 14, and a cap 32(cap to be removed prior to insertion) in one embodiment. The protectivesheath 26 extends through the fluid coupler and houses the sensor, forsensor insertion into a catheter. The protective sheath includes anoptional outlet hole 30 a, through which the sensor extends and a slot30 along a length of the protective sheath that communicates with theoutlet hole and enables the protective sheath to be removed after thesensor has been inserted into the host's body. The protective sheathincludes a hub 28 for ease of handling.

In some embodiments, the glucose sensor is utilized in combination withanother medical device (e.g., a medical device or access port that isalready coupled to, applied to, or connected to the host) in a hospitalor similar clinical setting. For example, a catheter can be insertedinto the host's vein or artery, wherein the catheter can is connected toadditional medical equipment. In an alternative example, the catheter isplaced in the host to provide quick access to the host's circulatorysystem (in the event of a need arising) and is simply capped. In anotherexample, a dialysis machine can be connected to the host's circulatorysystem. In another example, a central line can be connected to the host,for insertion of medical equipment at the heart (e.g., the medicalequipment reaches the heart through the vascular system, from aperipheral location such as a leg or arm pit).

In practice of coupling to a catheter, before insertion of the sensor,the access port is opened. In one exemplary embodiment of a pre-insertedcatheter that is capped, the cap is removed and the sensor inserted intothe catheter. The back end of the sensor system can be capped orattached to additional medical equipment (e.g., saline drip, bloodpressure transducer, dialysis machine, blood chemistry analysis device,etc.). In another exemplary embodiment, medical equipment (e.g., salinedrip, blood pressure transducer, dialysis machine, blood chemistryanalysis device, etc.) is already connected to the catheter. The medicalequipment is disconnected from the catheter, the sensor inserted into(and coupled to) the catheter and then the medical equipment reconnected(e.g., coupled to the back end of the sensor system).

In some embodiments, the sensor is inserted directly into the host'scirculatory system without a catheter or other medical device. In onesuch exemplary embodiment, the sheath covering the sensor is relativelyrigid and supports the sensor during insertion. After the sensor hasbeen inserted into the host's vein or artery, the supportive sheath isremoved, leaving the exposed sensor in the host's vein or artery. In analternative example, the sensor is inserted into a vascular accessdevice (e.g., with or without a catheter) and the sheath removed, toleave the sensor in the host's vein or artery (e.g., through thevascular access device).

In various embodiments, in practice, prior to insertion, the cap 32 overthe protective sheath is removed as the health care professional holdsthe glucose sensor by the fluid coupler 20. The protective sheath 26,which is generally more rigid than the sensor but more flexible than aneedle, is then threaded through the catheter so as to extend beyond thecatheter into the blood flow (e.g., by about 0.010 inches to about 1inches). The protective sheath is then removed by sliding the sensorthrough the (optional) outlet hole 30 a and slotted portion 30 of thesheath (e.g., by withdrawing the protective sheath by pulling the hub28). Thus the sensor remains within the catheter; and the fluid coupler20, which holds the sensor 14, is coupled to the catheter itself (viaits connector 18). Other medical devices can be coupled to the secondside of the fluid coupler as desired. The sensor electronics (e.g.,adjacent to the fluid coupler or otherwise coupled to the fluid coupler)are then operatively connected (e.g., wired or wirelessly) to the sensorfor proper sensor function as is known in the art.

In another embodiment, the catheter 12 includes a plurality ofperforations (e.g., holes) that allow the host's fluid (e.g., blood) toflow through the lumen 12 a of the catheter. The fluid flowing throughthe catheter can make contact with a sensor 14 inserted therein. In afurther embodiment, the sensor does not protrude out of the catheter'stip 12 b and the host's blood flowing through the perforated catheter'slumen contacts the sensor's electroactive surfaces.

In still another embodiment, the catheter 12 includes at least a firstlumen and a second lumen. The sensor 14 is configured for insertion intothe catheter's first lumen. The second lumen can be used for infusionsinto the host's circulatory system or sample removal without disturbingthe sensor within the first lumen.

FIGS. 2A-2F are schematic views of a sensor integrally formed(integrally incorporated) onto a surface of a catheter, in someexemplary embodiments. In some embodiments, the sensor can be integrallyformed on an exterior surface of the catheter. In other embodiments, thesensor can be integrally formed on an interior surface of the catheter(e.g., on a lumenal surface). In still other embodiments, the sensor canbe integrally formed on the sensor's tip (e.g., as indicated by 214 a).In yet other embodiments, the sensor can be integrally incorporated withthe catheter, for example by bonding a sensor of the type described inFIGS. 3A to 3C into an inner or outer surface of the catheter.

Generally, the sensor system is provided with a cap that covers thecatheter and in vivo portion of the integral sensor. A needle or trocharthat runs the length of the catheter supports the device duringinsertion into the host's blood stream. Prior to use, medical caregiverholds the device by the fluid connector 218 and removes the cap toexpose the in vivo portion of the device (e.g., the catheter). Thecaregiver inserts the in vivo portion of the device into one of thehost's veins or arteries (depending upon whether the catheter is anintravenous catheter or an arterial catheter). After insertion, theneedle is withdrawn from the device. The device is then capped orconnected to other medical equipment (e.g., saline bag, pressuretransducer, blood collection bag, total parenteral feeding, dialysisequipment, automated blood chemistry equipment, etc.). In somealternative embodiments, the sensor-integrated catheter can be incommunication (e.g., fluid communication) with the host's vascularsystem through a vascular access device.

In some embodiments, a glucose sensor system includes a sensingmechanism substantially similar to that described in U.S. PatentPublication No. US-2006-0020187-A1, which is incorporated herein byreference in its entirety; for example, with platinum working electrodeand silver reference electrode coiled there around. Alternatively, thereference electrode can be located remote from the working electrode soas not to be inserted into the host, and can be located, for example,within the fluid coupler, thereby allowing a smaller footprint in theportion of the sensor adapted for insertion into the body (e.g., bloodstream); for example, without a coiled or otherwise configured referenceelectrode proximal to the working electrode. Although a platinum workingelectrode is discussed, a variety of known working electrode materialscan be utilized (e.g., Platinum-Iridium or Iridium). When locatedremotely, the reference electrode can be located away from the workingelectrode (e.g., the electroactive portion) at any location and with anyconfiguration so as to maintain bodily and/or in fluid communicationtherewith as is appreciated by one skilled in the art.

In an alternative embodiment, the sensor tip 14 a includes an enlarged,atraumatic area, for example a dull or bulbous portion about two timesthe diameter of the sensor or larger. In one exemplary embodiment, theenlarged portion is created by heating, welding, crushing or bonding asubstantially rounded structure onto the tip of the sensor (e.g.,polymer or metal). In another exemplary embodiment, the tip of thesensor is heated (e.g., arc welded or flash-butt resistance welded) tocause the tip to enlarge (e.g., by melting). The enlarged portion can beof any atraumatic shape, such as but not limited to oval, round,cone-shaped, cylindrical, teardrop, etc. While not wishing to be boundby theory, it is believed that an atraumatic or enlarged area enablesenhanced stability of a small diameter sensor in the blood flow andensures that the sensor remains within the blood flow (e.g., to avoidpiercing a vessel wall and/or becoming inserted subluminally.)

In some embodiments, a second working electrode can be provided on thesensor for measuring baseline, and thereby subtracting the baseline fromthe first working electrode to obtain a glucose-only signal, asdisclosed in copending U.S. Patent Publication No. US-2005-0143635-A1and U.S. Patent Publication No. US-2007-0027385-A1, herein incorporatedby reference in their entirety.

Referring now to FIGS. 2A-2E in more detail, some embodiments of theanalyte sensor system include a catheter 212 adapted for inserting intoa host in a hospital or clinical setting, wherein the analyte sensor 214is built integrally with the catheter 212. For example, a glucose sensorcan be integrally formed on the catheter itself. FIGS. 2A-2B illustrateone embodiment, wherein the catheter 212 is configured both forinsertion into a host, and can be configured to couple to other medicaldevices on its ex vivo end. However, coupling to other medical devicesis not necessary. In some embodiments, the catheter includes a connector218 configured for connection to tubing or other medical devices, asdescribed herein. The embodiment shown in FIGS. 2A-2B includes two orthree electrodes 240 on the outer surface of the in vivo portion of thecatheter 212. In some embodiments, the catheter is perforated (asdescribed elsewhere herein) and at least one electrode is disposedwithin the lumen (not shown) of the perforated catheter. In someembodiments, the catheter includes a single lumen. In other embodiment,the catheter includes two or more lumens.

With reference to FIGS. 2C-2E, in some embodiments, at least one workingelectrode 240 is disposed on the exterior surface of the in vivo portionof the catheter. Alternatively, the at least one working electrode canbe disposed on an interior surface of the catheter, the tip of thecatheter, extend from the catheter, and the like. In general, thepreferred embodiments can be designed with any number of electrodes,including one or more counter electrodes, one or more referenceelectrodes, and/or one or more auxiliary working electrodes. In furtherembodiments, the electrodes can be of relatively larger or smallersurface area, depending upon their uses. In one example, a sensorincludes a working electrode and a reference electrode that has a largersurface area (relative to the surface area of the working electrode) onthe surface of the catheter. In another example, a sensor includes aworking electrode, a counter electrode, and a reference electrode sizedto have an increased surface area as compared to the working and/orcounter electrode. In some embodiments, the reference electrode isdisposed at a location remote from the working electrode, such as withinthe connector (e.g., coiled within the connector). In some embodiments,the reference electrode is located on the host's body (e.g., in bodycontact).

The electrodes 240 can be deposited on the catheter using any suitabletechniques known in the art, for example, thick or thin film depositiontechniques. The electrodes can be formed of any advantageous electrodematerials known in the art (e.g., platinum, platinum-iridium, palladium,graphite, gold, carbon, silver, silver-silver chloride, conductivepolymer, alloys, combinations thereof, and the like). In otherembodiments, one or more of the electrodes is formed from anelectrically conductive material (e.g., wire or foil comprisingplatinum, platinum-iridium, palladium, graphite, gold, carbon, silver,silver-silver chloride, conductive polymer, alloys, combinationsthereof, and the like) applied to the exterior surface of the catheter,such as but not limited twisting, coiling, rolling or adhering.

In some embodiments, the catheter is (wired or wirelessly) connected tosensor electronics (not shown, disposed on the catheter's connectorand/or remote from the catheter) so as to electrically connect theelectrodes on the catheter with the sensor electronics. The insertedcatheter (including the sensor integrally formed thereon) can beutilized by other medical devices for a variety of functions (e.g.,blood pressure monitor, drug delivery, etc).

While not wishing to be bound by theory, a number of the systems andmethods disclosed in the preferred embodiments (e.g., an analyte sensorto be disposed in communication with the host's blood), can be employedin transcutaneous (e.g., transdermal) or wholly implantable analytesensor devices. For example, the sensor could be integrally formed onthe in vivo portion of a subcutaneous device or a wholly implantabledevice. As another example, an enlarged surface area (e.g., bulbous end)can useful in the design of a transcutaneous analyte sensor.

Exemplary Sensor Configurations

Referring to FIGS. 3A to 3C, in some embodiments, the sensor can beconfigured similarly to the continuous analyte sensors disclosed inco-pending U.S. patent application Ser. No. 11/360,250 filed Feb. 22,2006 and entitled “ANALYTE SENSOR,” herein incorporated by reference inits entirety. The sensor includes a distal portion 342, also referred toas the in vivo portion, adapted for insertion into the catheter asdescribed above, and a proximal portion 340, also referred to as an exvivo portion, adapted to operably connect to the sensor electronics.Preferably, the sensor includes two or more electrodes: a workingelectrode 344 and at least one additional electrode, which can functionas a counter electrode and/or reference electrode, hereinafter referredto as the reference electrode 346. A membrane system is preferablydeposited over the electrodes, such as described in more detail withreference to FIGS. 3A to 3C, below.

FIG. 3B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 344 (e.g., awire) and a reference electrode 346 helically wound around the workingelectrode 344. An insulator 345 is disposed between the working andreference electrodes to provide electrical insulation therebetween.Certain portions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 343 can be formed in theinsulator to expose a portion of the working electrode 344 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 inches or less to about 0.010 inches ormore, for example, and is formed from, e.g., a plated insulator, aplated wire, or bulk electrically conductive material. Although theillustrated electrode configuration and associated text describe onepreferred method of forming a sensor, a variety of known sensorconfigurations can be employed with the analyte sensor system of thepreferred embodiments, such as U.S. Pat. No. 5,711,861 to Ward et al.,U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Sayet al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No.6,214,185 to Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunninghamet al., and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No.6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al.,U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 toMastrototaro et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al, forexample. All of the above patents are incorporated in their entiretyherein by reference and are not inclusive of all applicable analytesensors; in general, it should be understood that the disclosedembodiments are applicable to a variety of analyte sensorconfigurations. It is noted that much of the description of thepreferred embodiments, for example the membrane system described below,can be implemented not only with in vivo sensors, but also with in vitrosensors, such as blood glucose meters (SMBG).

In some embodiments, the working electrode comprises a wire formed froma conductive material, such as platinum, platinum-iridium, palladium,graphite, gold, carbon, conductive polymer, alloys, and the like.Although the electrodes can by formed by a variety of manufacturingtechniques (bulk metal processing, deposition of metal onto a substrate,and the like), it can be advantageous to form the electrodes from platedwire (e.g., platinum on steel wire) or bulk metal (e.g., platinum wire).It is believed that electrodes formed from bulk metal wire providesuperior performance (e.g., in contrast to deposited electrodes),including increased stability of assay, simplified manufacturability,resistance to contamination (e.g., which can be introduced in depositionprocesses), and improved surface reaction (e.g., due to purity ofmaterial) without peeling or delamination.

In some embodiments, the working electrode is formed of platinum-iridiumor iridium wire. In general, platinum-iridium and iridium materials aregenerally stronger (e.g., more resilient and less likely to fail due tostress or strain fracture or fatigue). It is believed thatplatinum-iridium and/or iridium materials can facilitate a wire with asmaller diameter to further decrease the maximum diameter (size) of thesensor (e.g., in vivo portion). Advantageously, a smaller sensordiameter both reduces the risk of clot or thrombus formation (or otherforeign body response) and allows the use of smaller catheters.

The electroactive window 343 of the working electrode 344 is configuredto measure the concentration of an analyte. In an enzymaticelectrochemical sensor for detecting glucose, for example, the workingelectrode measures the hydrogen peroxide produced by an enzyme catalyzedreaction of the analyte being detected and creates a measurableelectronic current For example, in the detection of glucose whereinglucose oxidase produces hydrogen peroxide as a byproduct, hydrogenperoxide reacts with the surface of the working electrode producing twoprotons (2H⁺), two electrons (2e⁻) and one molecule of oxygen (O₂),which produces the electronic current being detected.

In preferred embodiments, the working electrode 344 is covered with aninsulating material 345, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). While not wishing to bebound by theory, it is believed that the lubricious (e.g., smooth)coating (e.g., parylene) on the sensors of some embodiments contributesto minimal trauma and extended sensor life. While parylene coatings aregenerally preferred in some embodiments, any suitable insulatingmaterial can be used, for example, fluorinated polymers,polyethyleneterephthalate, polyurethane, polyimide, other nonconductingpolymers, and the like. Glass or ceramic materials can also be employed.Other materials suitable for use include surface energy modified coatingsystems such as are marketed under the trade names AMC18, AMC148,AMC141, and AMC321 by Advanced Materials Components Express ofBellafonte, Pa. In some alternative embodiments, however, the workingelectrode may not require a coating of insulator.

The reference electrode 346, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, and the like. In some embodiments, thereference electrode 346 is juxtapositioned and/or twisted with or aroundthe working electrode 344; however other configurations are alsopossible (e.g., coiled within the fluid connector, or an intradermal oron-skin reference electrode). In the illustrated embodiments, thereference electrode 346 is helically wound around the working electrode344. The assembly of wires is then optionally coated or adhered togetherwith an insulating material, similar to that described above, so as toprovide an insulating attachment.

In some embodiments, a silver wire is formed onto the sensor asdescribed above, and subsequently chloridized to form silver/silverchloride reference electrode. Advantageously, chloridizing the silverwire as described herein enables the manufacture of a referenceelectrode with optimal in vivo performance. Namely, by controlling thequantity and amount of chloridization of the silver to formsilver/silver chloride, improved break-in time, stability of thereference electrode, and extended life has been shown with someembodiments. Additionally, use of silver chloride as described aboveallows for relatively inexpensive and simple manufacture of thereference electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit),and the like, to expose the electroactive surfaces. Alternatively, aportion of the electrode can be masked prior to depositing the insulatorin order to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating, without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 3B, a radial window 343 is formedthrough the insulating material 345 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sectionsof electroactive surface of the reference electrode are exposed. Forexample, the sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.25 mm (about 0.01 inches)to about 0.375 mm (about 0.015 inches). In such embodiments, the exposedsurface area of the working electrode is preferably from about 0.000013in² (0.0000839 cm²) or less to about 0.0025 in² (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g., sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g., permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Patent PublicationNo. US-2005-0161346-A1, U.S. Patent Publication No. US-2005-0143635-A1,and U.S. Patent Publication No. US-2007-0027385-A1 describe some systemsand methods for implementing and using additional working, counter,and/or reference electrodes. In one implementation wherein the sensorcomprises two working electrodes, the two working electrodes arejuxtapositioned (e.g., extend parallel to each other), around which thereference electrode is disposed (e.g., helically wound). In someembodiments wherein two or more working electrodes are provided, theworking electrodes can be formed in a double-, triple-, quad-, etc.helix configuration along the length of the sensor (for example,surrounding a reference electrode, insulated rod, or other supportstructure). The resulting electrode system can be configured with anappropriate membrane system, wherein the first working electrode isconfigured to measure a first signal comprising glucose and baseline(e.g., background noise) and the additional working electrode isconfigured to measure a baseline signal consisting of baseline only(e.g., configured to be substantially similar to the first workingelectrode without an enzyme disposed thereon). In this way, the baselinesignal can be subtracted from the first signal to produce a glucose-onlysignal that is substantially not subject to fluctuations in the baselineand/or interfering species on the signal.

Although the embodiments of FIGS. 3A to 3C illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated. In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator therebetween. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator therebetween. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axle. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the protective slotted sheathis able to insert the sensor into the catheter and subsequently slideback over the sensor and release the sensor from the protective slottedsheath, without complex multi-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the catheter in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. Oneskilled in the art will appreciate that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

In addition to the above-described configurations, the referenceelectrode can be separated from the working electrode, and coiled withina portion of the fluid connector, in some embodiments. In anotherembodiment, the reference electrode is coiled within the fluid connectorand adjacent to its first side. In an alternative embodiment, thereference electrode is coiled within the fluid connector and adjacent toits second side. In such embodiments, the reference electrode is incontact with fluid, such as saline from a saline drip that is flowinginto the host, or such as blood that is being withdrawn from the host.While not wishing to be bound by theory, this configuration is believedto be advantageous because the sensor is thinner, allowing the use ofsmaller catheters and/or a reduced likelihood to thrombus production.

In another embodiment, the reference electrode 346 can be disposedfarther away from the electroactive portion of the working electrode 343(e.g., closer to the fluid connector). In some embodiments, thereference electrode is located proximal to or within the fluid coupler,such as but not limited to, coiled about the catheter adjacent to thefluid coupler or coiled within the fluid coupler and in contact withfluid flowing through the fluid coupler, such as saline. Theseconfigurations can also minimize at least a portion of the sensordiameter and thereby allow the use of smaller catheters and reduce therisk of clots.

In addition to the embodiments described above, the sensor can beconfigured with additional working electrodes as described in U.S.Patent Publication No. US-2005-0143635-A1, U.S. Pat. No. 7,081,195, andU.S. Patent Publication No. US-2007-0027385-A1, herein incorporated byreference in their entirety. For example, in one embodiment have anauxiliary working electrode, wherein the auxiliary working electrodecomprises a wire formed from a conductive material, such as describedwith reference to the glucose-measuring working electrode above.Preferably, the reference electrode, which can function as a referenceelectrode alone, or as a dual reference and counter electrode, is formedfrom silver, Silver/Silver chloride, and the like.

In some embodiments, the electrodes are juxtapositioned and/or twistedwith or around each other; however other configurations are alsopossible. In one example, the auxiliary working electrode and referenceelectrode can be helically wound around the glucose-measuring workingelectrode. Alternatively, the auxiliary working electrode and referenceelectrode can be formed as a double helix around a length of theglucose-measuring working electrode. The assembly of wires can then beoptionally coated together with an insulating material, similar to thatdescribed above, in order to provide an insulating attachment. Someportion of the coated assembly structure is then stripped, for exampleusing an excimer laser, chemical etching, and the like, to expose thenecessary electroactive surfaces. In some alternative embodiments,additional electrodes can be included within the assembly, for example,a three-electrode system (including separate reference and counterelectrodes) as is appreciated by one skilled in the art.

In some alternative embodiments, the sensor is configured as adual-electrode system. In one such dual-electrode system, a firstelectrode functions as a hydrogen peroxide sensor including a membranesystem containing glucose-oxidase disposed thereon, which operates asdescribed herein. A second electrode is a hydrogen peroxide sensor thatis configured similar to the first electrode, but with a modifiedmembrane system (without active enzyme, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the insertedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S. PatentPublication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some embodiments, the reference electrode can be disposed remotelyfrom the working electrode. In one embodiment, the reference electroderemains within the fluid flow, but is disposed within the fluid coupler.For example, the reference electrode can be coiled within the fluidcoupler such that it is contact with saline flowing into the host, butit is not in physical contact with the host's blood (except when bloodis withdrawn from the catheter). In another embodiment, the referenceelectrode is removed from fluid flow, but still maintains bodily fluidcontact. For example, the reference electrode can be wired to anadhesive patch that is adhered to the host, such that the referenceelectrode is in contact with the host's skin. In yet another embodiment,the reference electrode can be external from the system, such as but notlimited to in contact with the exterior of the ex vivo portion of thesystem, in fluid or electrical contact with a connected saline drip orother medical device, or in bodily contact, such as is generally donewith EKG electrical contacts. While not wishing to be bound by theory,it is believed to locating the reference electrode remotely from theworking electrode permits manufacture of a smaller sensor footprint(e.g., diameter) that will have relatively less affect on the host'sblood flow, such as less thrombosis, than a sensor having a relativelylarger footprint (e.g., wherein both the working electrode and thereference electrode are adjacent to each other and within the bloodpath).

In some embodiments of the sensor system, in vivo portion of the sensor(e.g., the tip 14 a) has an enlarged area (e.g., a bulbous, nailhead-shaped, football-shaped, cone-shaped, cylindrical, etc. portion) ascompared a substantial portion of the sensor (e.g., diameter of the invivo portion of the sensor). The sensor tip can be made bulbous by anyconvenient systems and methods known in the art, such as but not limitedto arc welding, crimping, smashing, welding, molding, heating, andplasma arc welding. While not wishing to be bound by theory, it isbelieved that an enlarged sensor tip (e.g., bulbous) will prevent vesselpiercing as the sensor is pushed forward into the vessel.

The sensor of the preferred embodiments is designed with a minimallyinvasive architecture so as to minimize reactions or effects on theblood flow (or on the sensor in the blood flow). Accordingly, the sensordesigns described herein, consider minimization of dimensions andarrangement of the electrodes and other components of the sensor system,particularly the in vivo portion of the sensor (or any portion of thesensor in fluid contact with the blood flow).

Accordingly, in some embodiments, a substantial portion of the in vivoportion of the sensor is designed with at least one dimension less thanabout 0.020, 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004 inches. Insome embodiments, a substantial portion of the sensor that is in fluidcontact with the blood flow is designed with at least one dimension lessthan about 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004, 0.003,0.002, 0.001 inches. As one exemplary embodiment, a sensor such asdescribed in more detail with reference to FIGS. 1A to 1C is formed froma 0.004 inch conductive wire (e.g., platinum) for a diameter of about0.004 inches along a substantial portion of the sensor (e.g., in vivoportion or fluid contact portion). As another exemplary embodiment, asensor such as described in more detail with reference to FIGS. 1A to 1Cis formed from a 0.004 inch conductive wire and vapor deposited with aninsulator material for a diameter of about 0.005 inches along asubstantial portion of the sensor (e.g., in vivo portion or fluidcontact portion), after which a desired electroactive surface area canbe exposed. In the above two exemplary embodiments, the referenceelectrode can be located remote from the working electrode (e.g., formedfrom the conductive wire). While the devices and methods describedherein are directed to use within the host's blood stream, one skilledin the art will recognize that the systems, configurations, methods andprinciples of operation described herein can be incorporated into otheranalyte sensing devices, such as but not limited to subcutaneous devicesor wholly implantable devices such as described in U.S. Publication2006-0016700, which is incorporated herein by reference in its entirety.

FIG. 3C is a cross section of the sensor shown in FIG. 3B, taken at lineC-C. Preferably, a membrane system (see FIG. 3C) is deposited over theelectroactive surfaces of the sensor and includes a plurality of domainsor layers, such as described in more detail below, with reference toFIGS. 3B and 3C. The membrane system can be deposited on the exposedelectroactive surfaces using known thin film techniques (for example,spraying, electro-depositing, dipping, and the like). In one exemplaryembodiment, each domain is deposited by dipping the sensor into asolution and drawing out the sensor at a speed that provides theappropriate domain thickness. In general, the membrane system can bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art.

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 347, an interference domain 348, an enzymedomain 349 (for example, including glucose oxidase), and a resistancedomain 350, as shown in FIG. 3C, and can include a high oxygensolubility domain, and/or a bioprotective domain (not shown), such as isdescribed in more detail in U.S. Patent Publication No.US-2005-0245799-A1, and such as is described in more detail below. Themembrane system can be deposited on the exposed electroactive surfacesusing known thin film techniques (for example, vapor deposition,spraying, electro-depositing, dipping, and the like). In alternativeembodiments, however, other vapor deposition processes (e.g., physicaland/or chemical vapor deposition processes) can be useful for providingone or more of the insulating and/or membrane layers, includingultrasonic vapor deposition, electrostatic deposition, evaporativedeposition, deposition by sputtering, pulsed laser deposition, highvelocity oxygen fuel deposition, thermal evaporator deposition, electronbeam evaporator deposition, deposition by reactive sputtering molecularbeam epitaxy, atmospheric pressure chemical vapor deposition (CVD),atomic layer CVD, hot wire CVD, low-pressure CVD, microwaveplasma-assisted CVD, plasma-enhanced CVD, rapid thermal CVD, remoteplasma-enhanced CVD, and ultra-high vacuum CVD, for example. However,the membrane system can be disposed over (or deposited on) theelectroactive surfaces using any known method, as will be appreciated byone skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as described above in connection with theporous layer, such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Patent Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 347 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 347 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode, which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 347 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 microns or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 3, 2.5, 2, or 1 microns, or less, to about 3.5, 4, 4.5, or 5microns or more. “Dry film” thickness refers to the thickness of a curedfilm cast from a coating formulation by standard coating techniques.

In certain embodiments, the electrode domain 347 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 347 is formed from ahydrophilic polymer (e.g., a polyamide, a polylactone, a polyimide, apolylactam, a functionalized polyamide, a functionalized polylactone, afunctionalized polyimide, a functionalized polylactam or a combinationthereof) that renders the electrode domain substantially morehydrophilic than an overlying domain, (e.g., interference domain, enzymedomain). In some embodiments, the electrode domain is formedsubstantially entirely and/or primarily from a hydrophilic polymer. Insome embodiments, the electrode domain is formed substantially entirelyfrom PVP. In some embodiments, the electrode domain is formed entirelyfrom a hydrophilic polymer. Useful hydrophilic polymers include but arenot limited to poly-N-vinylpyrrolidone (PVP), poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof andmixtures thereof. A blend of two or more hydrophilic polymers ispreferred in some embodiments. In some preferred embodiments, thehydrophilic polymer(s) is not crosslinked. In alternative embodiments,crosslinking is preferred, such as by adding a crosslinking agent, suchas but not limited to EDC, or by irradiation at a wavelength sufficientto promote crosslinking between the hydrophilic polymer molecules, whichis believed to create a more tortuous diffusion path through the domain.

An electrode domain formed from a hydrophilic polymer (e.g., PVP) hasbeen shown to substantially reduce break-in time of analyte sensors; forexample, a glucose sensor utilizing a cellulosic-based interferencedomain such as described in more detail elsewhere herein. In someembodiments, a uni-component electrode domain formed from a singlehydrophilic polymer (e.g., PVP) has been shown to substantially reducebreak-in time of a glucose sensor to less than about 2 hours, less thanabout 1 hour, less than about 20 minutes and/or substantiallyimmediately, such as exemplified in Examples 9 through 11 and 13.Generally, sensor break-in is the amount of time required (afterimplantation) for the sensor signal to become substantiallyrepresentative of the analyte concentration. Sensor break-in includesboth membrane break-in and electrochemical break-in, which are describedin more detail elsewhere herein. In some embodiments, break-in time isless than about 2 hours. In other embodiments, break-in time is lessthan about 1 hour. In still other embodiments, break-in time is lessthan about 30 minutes, less than about 20 minutes, less than about 15minutes, less than about 10 minutes, or less. In a preferred embodiment,sensor break-in occurs substantially immediately. Advantageously, inembodiments wherein the break-in time is about 0 minutes (substantiallyimmediately), the sensor can be inserted and begin providingsubstantially accurate analyte (e.g., glucose) concentrations almostimmediately post-insertion, for example, wherein membrane break-in doesnot limit start-up time.

While not wishing to be bound by theory, it is believed that providingan electrode domain that is substantially more hydrophilic than the nextmore distal membrane layer or domain (e.g., the overlaying domain; thelayer more distal to the electroactive surface than the electrodedomain, such as an interference domain or an enzyme domain) reduces thebreak-in time of an implanted sensor, by increasing the rate at whichthe membrane system is hydrated by the surrounding host tissue (seeExamples 8, 9, 10 and 12). While not wishing to be bound by theory, itis believed that, in general, increasing the amount of hydrophilicity ofthe electrode domain relative to the overlaying layer (e.g., the distallayer in contact with electrode domain, such as the interference domain,enzyme domain, etc.), increases the rate of water absorption, resultingin reduced sensor break-in time. The hydrophilicity of the electrodedomain can be substantially increased by the proper selection ofhydrophilic polymers, based on their hydrophilicity relative to eachother and relative to the overlaying layer (e.g., cellulosic-basedinterference domain), with preferred polymers being substantially morehydrophilic than the overlaying layer. In one exemplary embodiment, PVPforms the electrode domain, the interference domain is formed from ablend of cellulosic derivatives, such as but not limited to celluloseacetate butyrate and cellulose acetate; it is believed that since PVP issubstantially more hydrophilic than the cellulosic-based interferencedomain, the PVP rapidly draws water into the membrane to the electrodedomain, and enables the sensor to function with a desired sensitivityand accuracy and starting within a substantially reduced time periodafter implantation. Reductions in sensor break-in time reduce the amountof time a host must wait to obtain sensor readings, which isparticularly advantageous not only in ambulatory applications, butparticularly in hospital settings where time is critical.

While not wishing to be bound by theory, it is believed that when thewater absorption of the overlying domain (e.g., the domain overlying theelectrode domain) is less than the water absorption of the electrodedomain (e.g., during membrane equilibration), then the difference inwater absorption between the two domains will drive membraneequilibration and thus membrane break-in. Namely, increasing thedifference in hydrophilicity (e.g., between the two domains) results inan increase in the rate of water absorption, which, in turn, results ina decrease in membrane break-in time and/or sensor break-in time. Asdiscussed elsewhere herein, the relative hydrophilicity of the electrodedomain as compared to the overlying domain can be modulated by aselection of more hydrophilic materials for formation of the electrodedomain (and/or more hydrophobic materials for the overlying domain(s)).For example, an electrode domain with hydrophilic polymer capable ofabsorbing larger amounts of water can be selected instead of a secondhydrophilic polymer that is capable of absorbing less water than thefirst hydrophilic polymer. In some embodiments, the water contentdifference between the electrode domain and the overlying domain (e.g.,during or after membrane equilibration) is from about 1% or less toabout 90% or more. In other embodiments, the water content differencebetween the electrode domain and the overlying domain is from about 10%or less to about 80% or more. In still other embodiments, the watercontent difference between the electrode domain and the overlying domainis from about 30% or less to about 60% or more. In preferredembodiments, the electrode domain absorbs 5 wt. % or less to 95 wt. % ormore water, preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % toabout 55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % water than the adjacent(overlying) domain (e.g., the domain that is more distal to theelectroactive surface than the electrode domain).

In another example, the rate of water absorption by a polymer can beaffected by other factors, such as but not limited to the polymer'smolecular weight. For example, the rate of water absorption by PVP isdependent upon its molecular weight, which is typically from about 40kDa or less to about 360 kDa or more; with a lower molecular weight PVP(e.g., 40 kDa) absorbing water faster than a higher molecular weightPVP. Accordingly, modulating factors, such as molecular weight, thataffect the rate of water absorption by a polymer, can promote the properselection of materials for electrode domain fabrication. In oneembodiment, a lower molecular weight PVP is selected, to reduce break-intime.

Preferably, the electrode domain is deposited by known thin filmdeposition techniques (e.g., spray coating or dip-coating theelectroactive surfaces of the sensor). In some embodiments, theelectrode domain is formed by dip-coating the electroactive surfaces inan electrode domain solution (e.g., 5, 10, 15, 20, 25 or 30% or more PVPin deionized water) and curing the domain for a time of from about 15minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode domain solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode domainsolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode domain solution provide afunctional coating. However, values outside of those set forth above canbe acceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes. In anotherembodiment, the electroactive surfaces of the electrode system isdip-coated and cured at 50° C. under vacuum for 20 minutes a first time,followed by dip coating and curing at 50° C. under vacuum for 20 minutesa second time (two layers). In still other embodiments, theelectroactive surfaces can be dip-coated three or more times (three ormore layers). In other embodiments, the 1, 2, 3 or more layers of PVPare applied to the electroactive surfaces by spray coating or vapordeposition. In some embodiments, a crosslinking agent (e.g., EDC) can beadded to the electrode domain casting solution to promote crosslinkingwithin the domain (e.g., between electrode domain polymer components,latex, etc.). In some alternative embodiments however, no crosslinkingagent is used and the electrode domain is not substantially crosslinked.

In some embodiments, the deposited PVP electrode domain 347 has a “dryfilm” thickness of from about 0.05 microns or less to about 20 micronsor more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, andmore preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,4.5, or 5 microns.

Although an independent electrode domain 347 is described herein, insome embodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g., without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal (e.g., a non-analyte-related signal). This false positivesignal causes the host's analyte concentration (e.g., glucoseconcentration) to appear higher than the true analyte concentration.False-positive signal is a clinically significant problem in someconventional sensors. For example in a case of a dangerouslyhypoglycemic situation, wherein the host has ingested an interferent(e.g., acetaminophen), the artificially high glucose signal can lead thehost to believe that he is euglycemic (or, in some cases,hyperglycemic). As a result, the host can make inappropriate treatmentdecisions, such as taking no action, when the proper course of action isto begin eating. In another example, in the case of a euglycemic orhyperglycemic situation, wherein a host has consumed acetaminophen, anartificially high glucose signal caused by the acetaminophen can leadthe host to believe that his glucose concentration is much higher thanit truly is. Again, as a result of the artificially high glucose signal,the host can make inappropriate treatment decisions, such as givinghimself too much insulin, which in turn can lead to a dangeroushypoglycemic episode.

In preferred embodiments, an interference domain 348 is provided thatsubstantially restricts or blocks the flow of one or more interferingspecies therethrough; thereby substantially preventing artificial signalincreases. Some known interfering species for a glucose sensor, asdescribed in more detail herein, include acetaminophen, ascorbic acid,bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen,L-dopa, methyl dopa, salicylate, tetracycline, tolazamide, tolbutamide,triglycerides, and uric acid. In general, the interference domain of thepreferred embodiments is less permeable to one or more of theinterfering species than to the measured species, e.g., the product ofan enzymatic reaction that is measured at the electroactive surface(s),such as but not limited to H₂O₂.

In one embodiment, the interference domain 348 is formed from one ormore cellulosic derivatives. Cellulosic derivatives can include, but arenot limited to, cellulose esters and cellulose ethers. In general,cellulosic derivatives include polymers such as cellulose acetate,cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetatephthalate, cellulose acetate propionate, cellulose acetate trimellitate,and the like, as well as their copolymers and terpolymers with othercellulosic or non-cellulosic monomers. Cellulose is a polysaccharidepolymer of β-D-glucose. While cellulosic derivatives are generallypreferred, other polymeric polysaccharides having similar properties tocellulosic derivatives can also be employed in the preferredembodiments.

In one preferred embodiment, the interference domain 348 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of about 10,000 daltons to about 75,000 daltons, preferably fromabout 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000, 60,000,65,000, or 70,000 daltons, and more preferably about 20,000 daltons isemployed. In certain embodiments, however, higher or lower molecularweights can be preferred. In some embodiments, a blend of two or morecellulose acetate butyrates having different molecular weights ispreferred. While a “blend” as defined herein (a composition of two ormore substances that are not substantially chemically combined with eachother and are capable of being separated) is generally preferred, incertain embodiments a single polymer incorporating differentconstituents (e.g., separate constituents as monomeric units and/orsubstituents on a single polymer chain) can be employed instead.Additionally, a casting solution or dispersion of cellulose acetatebutyrate at a wt. % of from about 5% to about 25%, preferably from about5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% to about 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%, and more preferably from about5% to about 15% is preferred. Preferably, the casting solution includesa solvent or solvent system, for example an acetone:ethanol solventsystem. Higher or lower concentrations can be preferred in certainembodiments. In alternative embodiments, a single solvent (e.g.,acetone) is used to form a symmetrical membrane domain. A single solventis used in casting solutions for forming symmetric membrane layer(s). Aplurality of layers of cellulose acetate butyrate can be advantageouslycombined to form the interference domain in some embodiments, forexample, three layers can be employed. It can be desirable to employ amixture of cellulose acetate butyrate components with differentmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate butyrate from different solutions comprising celluloseacetate butyrate of different molecular weights, differentconcentrations, and/or different chemistries (e.g. functional groups).It can also be desirable to include additional substances in the castingsolutions or dispersions, e.g., functionalizing agents, crosslinkingagents, other polymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain 348 is formedfrom cellulose acetate. Cellulose acetate with a molecular weight ofabout 30,000 daltons or less to about 100,000 daltons or more,preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000,60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000daltons, and more preferably about 50,000 daltons is preferred. In someembodiments, a blend of two or more cellulose acetates having differentmolecular weights is preferred. Additionally, a casting solution ordispersion of cellulose acetate at a weight percent of about 3% to about10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5%to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about 8%is preferred. In certain embodiments, however, higher or lower molecularweights and/or cellulose acetate weight percentages can be preferred. Itcan be desirable to employ a mixture of cellulose acetates withmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate from different solutions comprising cellulose acetatesof different molecular weights, different concentrations, or differentchemistries (e.g. functional groups). It can also be desirable toinclude additional substances in the casting solutions or dispersionssuch as described in more detail above.

In addition to forming an interference domain from only celluloseacetate(s) or only cellulose acetate butyrate(s), the interferencedomain 348 can be formed from combinations or blends of cellulosicderivatives, such as but not limited to cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate. In some embodiments, a blend ofcellulosic derivatives (for formation of an interference domain)includes up to about 10 wt. % or more of cellulose acetate. For example,about 1, 2, 3, 4, 5, 6, 7, 8, 9 wt. % or more cellulose acetate ispreferred, in some embodiments. In some embodiments, the cellulosicderivatives blend includes from about 90 wt. % or less to about 100 wt.% cellulose acetate butyrate. For example, in some embodiments, theblend includes about 91, 92, 93, 94, 95, 96, 97, 98 or 99 wt. %cellulose acetate butyrate. In some embodiments, the cellulosicderivative blend includes from about 1.5, 2.0, 2.5, 3.0 or 3.5 wt. %cellulose acetate to about 98.5, 98.0, 97.5, 97.0 or 96.5 wt. %cellulose acetate butyrate. In other embodiments, the blend includesfrom about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 wt. % cellulose acetateto about 96, 95.5, 95, 94.5, 94, 93.3, 93, 92.5 or 92 wt. % celluloseacetate butyrate. In still other embodiments, the blend includes fromabout 8.5, 9.0, 9.5, 10.0, 10.5 or 11.0 wt. % cellulose acetate to about91.5, 91.0, 90.5, 90, 89.5 or 89 wt. % cellulose acetate butyrate.

In some embodiments, preferred blends of cellulose acetate and celluloseacetate butyrate contain from about 1.5 parts or less to about 60 partsor more cellulose acetate butyrate to one part of cellulose acetate. Insome embodiments, a blend contains from about 2 parts to about 40 partscellulose acetate butyrate to one part cellulose acetate. In otherembodiments, about 4, 6, 8, 10, 12, 14, 16, 18 or 20 parts celluloseacetate butyrate to one part cellulose acetate is preferred forformation of the interference domain 348. In still other embodiments, ablend having from 22, 24, 26, 28, 30, 32, 34, 36 or 38 parts celluloseacetate butyrate to one part cellulose acetate is preferred. As isdiscussed elsewhere herein, cellulose acetate butyrate is relativelymore hydrophobic than cellulose acetate. Accordingly, the celluloseacetate/cellulose acetate butyrate blend contains substantially morehydrophobic than hydrophilic components.

Cellulose acetate butyrate is a cellulosic polymer having both acetyland butyl groups, in addition to hydroxyl groups. Acetyl groups are morehydrophilic than butyl groups, and hydroxyl groups are more hydrophilicthan both acetyl and butyl groups. Accordingly, the relative amounts ofacetyl, butyl and hydroxyl groups can be used to modulate thehydrophilicity/hydrophobicity of the cellulose acetate butyrate of thecellulose acetate/cellulose acetate butyrate blend. A cellulose acetatebutyrate can be selected based on the compound's relative amounts ofacetate, butyrate and hydroxyl groups; and a cellulose acetate can beselected based on the compounds relative amounts of acetate and hydroxylgroups. For example, in some embodiments, a cellulose acetate butyratehaving about 35% or less acetyl groups, about 10% to about 25% butylgroups, and hydroxyl groups making up the remainder is preferred forformation of the interference domain 348. In other embodiments acellulose acetate butyrate having from about 25% to about 34% acetylgroups and from about 15 to about 20% butyl groups is preferred. Instill other embodiments, the preferred cellulose acetate butyratecontains from about 28% to about 30% acetyl groups and from about 16 toabout 18% butyl groups. In yet another embodiment, the cellulose acetatebutyrate can have no acetate groups and from about 20% to about 60%butyrate groups. In yet another embodiment, the cellulose acetatebutyrate has about 55% butyrate groups and no acetate groups.

While an asymmetric interference domain can be used in some alternativeembodiments, a symmetrical interference domain 348 (e.g., ofcellulosic-derivative blends, such as but not limited to blends ofcellulose acetate components and cellulose acetate butyrate components)is preferred in some embodiments. Symmetrical membranes are uniformthroughout their entire structure, without gradients of pore densitiesor sizes, or a skin on one side but not the other, for example. Invarious embodiments, a symmetrical interference domain 348 can be formedby the appropriate selection of a solvent (e.g., no anti-solvent isused), for making the casting solution. Appropriate solvents includesolvents belonging to the ketone family that are able to solvate thecellulose acetate and cellulose acetate butyrate. The solvents includebut are not limited to acetone, methyl ethyl ketone, methyl n-propylketone, cyclohexanone, and diacetone alcohol. Other solvents, such asfurans (e.g., tetra-hydro-furan and 1,4-dioxane), may be preferred insome embodiments. In one exemplary embodiment, from about 7 wt. % toabout 9 wt. % solids (e.g., a blend of cellulosic derivatives, such ascellulose acetate and cellulose acetate butyrate) are blended with asingle solvent (e.g., acetone), to form the casting solution for asymmetrical interference domain. In another embodiment, from about 10 toabout 15% solids are blended with acetone to form the casting solution.In yet another embodiment, from about 16 to about 18% solids are blendedwith acetone to form the casting solution. A relatively lower or greaterweight percent of solids is preferred to form the casting solution, insome embodiments.

The casting solution can be applied either directly to the electroactivesurface(s) of the sensor or on top of an electrode domain layer (ifincluded in the membrane system). The casting solution can be appliedusing any known thin film technique, as discussed elsewhere herein.Additionally, in various embodiments, a symmetrical interference domain348 includes at least one layer; and in some embodiments, two, three ormore layers are formed by the sequential application and curing of thecasting solution.

The concentration of solids in the casting solution can be adjusted todeposit a sufficient amount of solids on the electrode in one layer(e.g., in one dip or spray) to form a membrane layer with sufficientblocking ability, such that the equivalent glucose signal of aninterferent (e.g., compounds with an oxidation or reduction potentialthat overlaps with that of the measured species (e.g., H₂O₂)), measuredby the sensor, is about 60 mg/dL or less. For example, in someembodiments, the casting solution's percentage of solids is adjustedsuch that only a single layer (e.g., dip one time) is required todeposit a sufficient amount of the cellulose acetate/cellulose acetatebutyrate blend to form a functional symmetric interference domain thatsubstantially blocks passage therethrough of at least one interferent,such as but not limited to acetaminophen, ascorbic acid, dopamine,ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uricacid, ephedrine, L-dopa, methyl dopa and tolazamide. In someembodiments, the amount of interference domain material deposited by assingle dip is sufficient to reduce the equivalent glucose signal of theinterferant (e.g., measured by the sensor) to about 60 mg/dl or less. Inpreferred embodiments, the interferent's equivalent glucose signalresponse (measured by the sensor) is 50 mg/dl or less. In more preferredembodiments, the interferent produces an equivalent glucose signalresponse of 40 mg/dl or less. In still more preferred embodiments, theinterferent produces an equivalent glucose signal response of less thanabout 30, 20 or 10 mg/dl. In one exemplary embodiment, the interferencedomain is configured to substantially block acetaminophen passagetherethrough, wherein the equivalent glucose signal response of theacetaminophen is less than about 30 mg/dl.

In alternative embodiments, the interference domain 348 is configured tosubstantially block a therapeutic dose of acetaminophen. The term“therapeutic dose” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the quantity of any substance required toeffect the cure of a disease, to relieve pain, or that will correct themanifestations of a deficiency of a particular factor in the diet, suchas the effective dose used with therapeutically applied compounds, suchas drugs. For example, a therapeutic dose of acetaminophen can be anamount of acetaminophen required to relieve headache pain or reduce afever. As a further example, 1,000 mg of acetaminophen taken orally,such as by swallowing two 500 mg tablets of acetaminophen, is thetherapeutic dose frequently taken for headaches. In some embodiments,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 60 mg/dl. In a preferred embodiment,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 40 mg/dl. In a more preferredembodiment, the interference membrane is configured to block atherapeutic dose of acetaminophen, wherein the equivalent glucose signalresponse of the acetaminophen is less than about 30 mg/dl.

While not wishing to be bound by theory, it is believed that, withrespect to symmetrical cellulosic-based membranes, there is an inverselyproportional balance between interferent blocking and analytesensitivity. Namely, changes to the interference domain configurationthat increase interferent blocking can result in a correspondingdecrease in sensor sensitivity. Sensor sensitivity is discussed in moredetail elsewhere herein. It is believed that the balance betweeninterferent blocking and sensor sensitivity is dependent upon therelative proportions of hydrophobic and hydrophilic components of themembrane layer (e.g., the interference domain), with sensors having morehydrophobic interference domains having increased interferent blockingbut reduces sensitivity; and sensors having more hydrophilicinterference domains having reduced interferent blocking but increasedsensitivity. It is believed that the hydrophobic and hydrophiliccomponents of the interference domain can be balanced, to promote adesired level of interferent blocking while at the same time maintaininga desired level of analyte sensitivity. The interference domainhydrophobe-hydrophile balance can be manipulated and/or maintained bythe proper selection and blending of the hydrophilic and hydrophobicinterference domain components (e.g., cellulosic derivatives havingacetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl,carboxymethyl, and/or carboxyethyl groups). For example, celluloseacetate is relatively more hydrophilic than cellulose acetate butyrate.In some embodiments, increasing the percentage of cellulose acetate (orreducing the percentage of cellulose acetate butyrate) can increase thehydrophilicity of the cellulose acetate/cellulose acetate butyrateblend, which promotes increased permeability to hydrophilic species,such as but not limited to glucose, H₂O₂ and some interferents (e.g.,acetaminophen). In another embodiment, the percentage of celluloseacetate butyrate is increased to increase blocking of interferants, butless permeability to some desired molecules, such as H₂O₂ and glucose,is also reduced.

One method, of manipulating the hydrophobe-hydrophile balance of theinterference domain, is to select the appropriate percentages of acetylgroups (relatively more hydrophilic than butyl groups), butyl groups(relatively more hydrophobic than acetyl groups) and hydroxyl groups ofthe cellulose acetate butyrate used to form the interference domain 348.For example, increasing the percentage of acetate groups on thecellulose acetate butyrate will make the cellulose acetate butyrate morehydrophilic. In another example, increasing the percentage of butylgroups on the cellulose acetate butyrate will make the cellulose acetatebutyrate more hydrophobic. In yet another example, increasing thepercentage of hydroxyl groups will increase the hydrophilicity of thecellulose acetate butyrate. Accordingly, the selection of a celluloseacetate butyrate that is more or less hydrophilic (or more or lesshydrophobic) can modulate the over-all hydrophilicity of the celluloseacetate/cellulose acetate butyrate blend. In one exemplary embodiment,an interference domain can be configured to be relatively morehydrophobic (and therefore block interferants more strongly) by reducingthe percentage of acetyl or hydroxyl groups or by increasing thepercentage of butyl groups on the cellulose acetate butyrate used in thecasting solution (while maintaining the relative ratio of celluloseacetate to cellulose acetate butyrate).

In some alternative embodiments, the interference domain 348 is formedof a blend of cellulosic derivatives, wherein the hydrophilic andhydrophobic components of the interference domain are balanced, suchthat the glucose sensitivity is from about 1 pA/mg/dL to about 100pA/mg/dL, and at least one interferent is sufficiently blocked frompassage through the interference domain such that the equivalent glucosesignal response of the at least one interferent is less than about 60mg/dL. In a preferred embodiment, the glucose sensitivity is from about5 pA/mg/dL to about 25 pA/mg/dL. In a more preferred embodiments, theglucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL andthe equivalent glucose signal response of the at least one interferentis less than about 40 mg/dL. In a still more preferred embodiments, theglucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL andthe equivalent glucose signal response of the at least one interferentis less than about 30 mg/dL. In some embodiments, the balance betweenhydrophilic and hydrophobic components of the interference domain can beachieved by adjusting the amounts of hydrophilic and hydrophobiccomponents, relative to each other, as well as adjusting the hydrophilicand hydrophobic groups (e.g., acetyl, butyryl, propionyl, methoxy,ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups) ofthe components themselves (e.g., cellulosic derivatives, such as but notlimited to cellulose acetate and cellulose acetate butyrate).

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 348. Asone example, a layer of a 5 wt. % Nafion® casting solution was appliedover a previously applied (e.g., and cured) layer of 8 wt. % celluloseacetate, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 348 of the preferredembodiments. In general, the formation of the interference domain on asurface utilizes a solvent or solvent system, in order to solvate thecellulosic derivative(s) (or other polymer) prior to film formationthereon. In preferred embodiments, acetone and ethanol are used assolvents for cellulose acetate; however one skilled in the artappreciates the numerous solvents that are suitable for use withcellulosic derivatives (and other polymers). Additionally, one skilledin the art appreciates that the preferred relative amounts of solventcan be dependent upon the cellulosic derivative (or other polymer) used,its molecular weight, its method of deposition, its desired thickness,and the like. However, a percent solute of from about 1 wt. % to about25 wt. % is preferably used to form the interference domain solution soas to yield an interference domain having the desired properties. Thecellulosic derivative (or other polymer) used, its molecular weight,method of deposition, and desired thickness can be adjusted, dependingupon one or more other of the parameters, and can be varied accordinglyas is appreciated by one skilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain 348 includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of high molecular weight species.The interference domain 48 is permeable to relatively low molecularweight substances, such as hydrogen peroxide, but restricts the passageof higher molecular weight substances, including glucose and ascorbicacid. Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Pat. No. 7,074,307, U.S. PatentPublication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195, and U.S.Patent Publication No. US-2005-0143635-A1. In some alternativeembodiments, a distinct interference domain is not included.

In some embodiments, the interference domain 348 is deposited eitherdirectly onto the electroactive surfaces of the sensor or onto thedistal surface of the electrode domain, for a domain thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 1, 1.5 or 2 microns to about 2.5 or 3 microns. Thickermembranes can also be desirable in certain embodiments, but thinnermembranes are generally preferred because they have a lower impact onthe rate of diffusion of hydrogen peroxide from the enzyme membrane tothe electrodes

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain 348 is deposited by spray or dip coating. In oneexemplary embodiment of a needle-type (transcutaneous) sensor such asdescribed herein, the interference domain is formed by dip coating thesensor into an interference domain solution using an insertion rate offrom about 0.5 inch/min to about 60 inches/min, preferably 1 inch/min, adwell time of from about 0 minute to about 2 minutes, preferably about 1minute, and a withdrawal rate of from about 0.5 inch/minute to about 60inches/minute, preferably about 1 inch/minute, and curing (drying) thedomain from about 1 minute to about 30 minutes, preferably from about 3minutes to about 15 minutes (and can be accomplished at room temperatureor under vacuum (e.g., 20 to 30 mmHg)). In one exemplary embodimentincluding cellulose acetate butyrate interference domain, a 3-minutecure (i.e., dry) time is preferred between each layer applied. Inanother exemplary embodiment employing a cellulose acetate interferencedomain, a 15 minute cure (i.e., dry) time is preferred between eachlayer applied.

In some embodiments, the dip process can be repeated at least one timeand up to 10 times or more. In other embodiments, only one dip ispreferred. The preferred number of repeated dip processes depends uponthe cellulosic derivative(s) used, their concentration, conditionsduring deposition (e.g., dipping) and the desired thickness (e.g.,sufficient thickness to provide functional blocking of certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness, however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In another embodiment, an interferencedomain is formed from 1 layer of a blend of cellulose acetate andcellulose acetate butyrate. In alternative embodiments, the interferencedomain can be formed using any known method and combination of celluloseacetate and cellulose acetate butyrate, as will be appreciated by oneskilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 348. In some embodiments, theinterference domain 348 of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 349 disposed more distally from the electroactive surfaces thanthe interference domain 348; however other configurations can bedesirable. In the preferred embodiments, the enzyme domain provides anenzyme to catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Patent Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating isused to deposit the enzyme domain at room temperature, a preferredinsertion rate of from about 0.25 inch per minute to about 3 inches perminute, with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at 50° C. under vacuum for 20 minutes. However, in someembodiments, the enzyme domain can be formed by dip coating and/or spraycoating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 350 disposed more distal from the electroactive surfaces than theenzyme domain. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21 (1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Patent PublicationNo. US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In some embodiments, the resistance domain is formed from a siliconepolymer modified to allow analyte (e.g., glucose) transport.

In some embodiments, the resistance domain is formed from a siliconepolymer/hydrophobic-hydrophilic polymer blend. In one embodiment, Thehydrophobic-hydrophilic polymer for use in the blend may be any suitablehydrophobic-hydrophilic polymer, including but not limited to componentssuch as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers such as polyethyleneglycol or polypropylene oxide, and copolymers thereof, including, forexample, di-block, tri-block, alternating, random, comb, star,dendritic, and graft copolymers (block copolymers are discussed in U.S.Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein byreference). In one embodiment, the hydrophobic-hydrophilic polymer is acopolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).Suitable such polymers include, but are not limited to, PEO-PPO diblockcopolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblockcopolymers, alternating block copolymers of PEO-PPO, random copolymersof ethylene oxide and propylene oxide, and blends thereof. In someembodiments, the copolymers may be optionally substituted with hydroxysubstituents. Commercially available examples of PEO and PPO copolymersinclude the PLURONIC® brand of polymers available from BASF®. In oneembodiment, PLURONIC® F-127 is used. Other PLURONIC® polymers includePPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Othersuitable commercial polymers include, but are not limited to,SYNPERONICS® products available from UNIQEMA®. Co-pending U.S. patentapplication Ser. No. 11/404,417 and entitled, “SILICONE BASED MEMBRANESFOR USE IN IMPLANTABLE GLUCOSE SENSORS,” which is incorporated herein byreference in its entirety, describes systems and methods suitable forthe resistance and/or other domains of the membrane system of thepreferred embodiments.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In another preferred embodiment, physical vapor deposition (e.g.,ultrasonic vapor deposition) is used for coating one or more of themembrane domain(s) onto the electrodes, wherein the vapor depositionapparatus and process include an ultrasonic nozzle that produces a mistof micro-droplets in a vacuum chamber. In these embodiments, themicro-droplets move turbulently within the vacuum chamber, isotropicallyimpacting and adhering to the surface of the substrate. Advantageously,vapor deposition as described above can be implemented to provide highproduction throughput of membrane deposition processes (e.g., at leastabout 20 to about 200 or more electrodes per chamber), greaterconsistency of the membrane on each sensor, and increased uniformity ofsensor performance, for example, as described below.

In some embodiments, depositing the resistance domain (for example, asdescribed in the preferred embodiments above) includes formation of amembrane system that substantially blocks or resists ascorbate (a knownelectrochemical interferant in hydrogen peroxide-measuring glucosesensors). While not wishing to be bound by theory, it is believed thatduring the process of depositing the resistance domain as described inthe preferred embodiments, a structural morphology is formed that ischaracterized in that ascorbate does not substantially permeatetherethrough.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° C. can typically provide adequate coverage by theresistance domain. Spraying the resistance domain material and rotatingthe sensor at least two times by 120° provides even greater coverage(one layer of 360° coverage), thereby ensuring resistivity to glucose,such as is described in more detail above.

In preferred embodiments, the resistance domain is spray coated andsubsequently cured for a time of from about 15 minutes to about 90minutes at a temperature of from about 40° C. to about 60° C. (and canbe accomplished under vacuum (e.g., from 20 to 30 mmHg)). A cure time ofup to about 90 minutes or more can be advantageous to ensure completedrying of the resistance domain.

In one embodiment, the resistance domain is formed by spray coating atleast six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip coating or spray coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.Additionally, curing in a convention oven can also be employed.

In certain embodiments, a variable frequency microwave oven can be usedto cure the membrane domains/layers. In general, microwave ovensdirectly excite the rotational mode of solvents. Consequently, microwaveovens cure coatings from the inside out rather than from the outside inas with conventional convection ovens. This direct rotational modeexcitation is responsible for the typically observed “fast” curingwithin a microwave oven. In contrast to conventional microwave ovens,which rely upon a fixed frequency of emission that can cause arcing ofdielectric (metallic) substrates if placed within a conventionalmicrowave oven, Variable Frequency Microwave (VFM) ovens emit thousandsof frequencies within 100 milliseconds, which substantially eliminatesarcing of dielectric substrates. Consequently, the membranedomains/layers can be cured even after deposition on metallic electrodesas described herein. While not wishing to be bound by theory, it isbelieve that VFM curing can increase the rate and completeness ofsolvent evaporation from a liquid membrane solution applied to a sensor,as compared to the rate and completeness of solvent evaporation observedfor curing in conventional convection ovens.

In certain embodiments, VFM is can be used together with convection ovencuring to further accelerate cure time. In some sensor applicationswherein the membrane is cured prior to application on the electrode(see, for example, U.S. Patent Publication No. US-2005-0245799-A1, whichis incorporated herein by reference in its entirety), conventionalmicrowave ovens (e.g., fixed frequency microwave ovens) can be used tocure the membrane layer.

Treatment of Interference Domain/Membrane System

Although the above-described methods generally include a curing step information of the membrane system, including the interference domain, thepreferred embodiments further include an additional treatment step,which can be performed directly after the formation of the interferencedomain and/or some time after the formation of the entire membranesystem (or anytime in between). In some embodiments, the additionaltreatment step is performed during (or in combination with)sterilization of the sensor.

In some embodiments, the membrane system (or interference domain) istreated by exposure to ionizing radiation, for example, electron beamradiation, UV radiation, X-ray radiation, gamma radiation, and the like.Alternatively, the membrane can be exposed to visible light whensuitable photoinitiators are incorporated into the interference domain.While not wishing to be bound by theory, it is believed that exposingthe interference domain to ionizing radiation substantially crosslinksthe interference domain and thereby creates a tighter, less permeablenetwork than an interference domain that has not been exposed toionizing radiation.

In some embodiments, the membrane system (or interference domain) iscrosslinked by forming free radicals, which may include the use ofionizing radiation, thermal initiators, chemical initiators,photoinitiators (e.g., UV and visible light), and the like. Any suitableinitiator or any suitable initiator system can be employed, for example,α-hydroxyketone, α-aminoketone, ammonium persulfate (APS), redox systemssuch as APS/bisulfite, or potassium permanganate. Suitable thermalinitiators include but are not limited to potassium persulfate, ammoniumpersulfate, sodium persulfate, and mixtures thereof.

In embodiments wherein electron beam radiation is used to treat themembrane system (or interference domain), a preferred exposure time isfrom about 6 k or 12 kGy to about 25 or 50 kGy, more preferably about 25kGy. However, one skilled in the art appreciates that choice ofmolecular weight, composition of cellulosic derivative (or otherpolymer), and/or the thickness of the layer can affect the preferredexposure time of membrane to radiation. Preferably, the exposure issufficient for substantially crosslinking the interference domain toform free radicals, but does not destroy or significantly break down themembrane or does not significantly damage the underlying electroactivesurfaces.

In embodiments wherein UV radiation is employed to treat the membrane,UV rays from about 200 nm to about 400 nm are preferred; however valuesoutside of this range can be employed in certain embodiments, dependentupon the cellulosic derivative and/or other polymer used.

In some embodiments, for example, wherein photoinitiators are employedto crosslink the interference domain, one or more additional domains canbe provided adjacent to the interference domain for preventingdelamination that may be caused by the crosslinking treatment. Theseadditional domains can be “tie layers” (i.e., film layers that enhanceadhesion of the interference domain to other domains of the membranesystem). In one exemplary embodiment, a membrane system is formed thatincludes the following domains: resistance domain, enzyme domain,electrode domain, and cellulosic-based interference domain, wherein theelectrode domain is configured to ensure adhesion between the enzymedomain and the interference domain. In embodiments whereinphotoinitiators are employed to crosslink the interference domain, UVradiation of greater than about 290 nm is preferred. Additionally, fromabout 0.01 to about 1 wt % photoinitiator is preferred weight-to-weightwith a preselected cellulosic polymer (e.g., cellulose acetate); howevervalues outside of this range can be desirable dependent upon thecellulosic polymer selected.

In general, sterilization of the transcutaneous sensor can be completedafter final assembly, utilizing methods such as electron beam radiation,gamma radiation, glutaraldehyde treatment, and the like. The sensor canbe sterilized prior to or after packaging. In an alternative embodiment,one or more sensors can be sterilized using variable frequency microwavechamber(s), which can increase the speed and reduce the cost of thesterilization process. In another alternative embodiment, one or moresensors can be sterilized using ethylene oxide (EtO) gas sterilization,for example, by treating with 100% ethylene oxide, which can be usedwhen the sensor electronics are not detachably connected to the sensorand/or when the sensor electronics must undergo a sterilization process.In one embodiment, one or more packaged sets of transcutaneous sensors(e.g., 1, 2, 3, 4, or 5 sensors or more) are sterilized simultaneously.

Therapeutic Agents

A variety of therapeutic (bioactive) agents can be used with the analytesensor system of the preferred embodiments, such as the analyte sensorsystem of the embodiments shown in FIGS. 1A-3C. In some embodiments, thetherapeutic agent is an anticoagulant. The term “anticoagulant” as usedherein is a broad term, and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art (and is not to belimited to a special or customized meaning), and refers withoutlimitation to a substance the prevents coagulation (e.g., minimizes,reduces, or stops clotting of blood). In some embodiments, ananticoagulant is included in the analyte sensor system to preventcoagulation within or on the sensor (e.g., within or on the catheter orwithin or on the sensor). Suitable anticoagulants for incorporation intothe sensor system include, but are not limited to, vitamin K antagonists(e.g., Acenocoumarol, Clorindione, Dicumarol (Dicoumarol), Diphenadione,Ethyl biscoumacetate, Phenprocoumon, Phenindione, Tioclomarol, orWarfarin), heparin group anticoagulants (e.g., Platelet aggregationinhibitors: Antithrombin III, Bemiparin, Dalteparin, Danaparoid,Enoxaparin, Heparin, Nadroparin, Parnaparin, Reviparin, Sulodexide,Tinzaparin), other platelet aggregation inhibitors (e.g., Abciximab,Acetylsalicylic acid (Aspirin), Aloxiprin, Beraprost, Ditazole,Carbasalate calcium, Cloricromen, Clopidogrel, Dipyridamole,Epoprostenol, Eptifibatide, Indobufen, Iloprost, Picotamide,Ticlopidine, Tirofiban, Treprostinil, Triflusal), enzymes (e.g.,Alteplase, Ancrod, Anistreplase, Brinase, Drotrecogin alfa,Fibrinolysin, Protein C, Reteplase, Saruplase, Streptokinase,Tenecteplase, Urokinase), direct thrombin inhibitors (e.g., Argatroban,Bivalirudin, Desirudin, Lepirudin, Melagatran, Ximelagatran, otherantithrombotics (e.g., Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, Rivaroxaban) and the like.

In one embodiment, heparin is incorporated into the analyte sensorsystem. In a further embodiment, heparin is coated on the catheter(inner and/or outer diameter) and/or sensor, for example, by dipping orspraying. While not wishing to be bound by theory, it is believed thatheparin coated on the catheter and/or sensor prevents aggregation andclotting of blood on the analyte sensor system, thereby preventingthromboembolization (e.g., prevention of blood flow by the thrombus orclot) and/or subsequent complications. In another embodiment, anantimicrobial is coated on the catheter (inner and/or outer diameter)and/or sensor.

In some embodiments, the therapeutic agent is an antimicrobial. The term“antimicrobial agent” as used in the preferred embodiments meansantibiotics, antiseptics, disinfectants and synthetic moieties, andcombinations thereof, that are soluble in organic solvents such asalcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid,methylene chloride and chloroform.

Classes of antibiotics that can be used include tetracyclines (i.e.minocycline), rifamycins (i.e. rifampin), macrolides (i.e.erythromycin), penicillins (i.e. nafeillin), cephalosporins (i.e.cefazolin), other beta-lactam antibiotics (i.e. imipenem, aztreonam),aminoglycosides (i.e. gentamicin), chloramphenicol, sulfonamides (i.e.sulfamethoxazole), glycopeptides (i.e. vancomycin), quinolones (i.e.ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin,mupirocin, polyenes (i.e. amphotericin B), azoles (i.e. fluconazole) andbeta-lactam inhibitors (i.e. sulbactam).

Examples of specific antibiotics that can be used include minocycline,rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam,gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin,clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid,sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin,temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,amphotericin B. fluconazole, itraconazole, ketoconazole, and nystatin.

Examples of antiseptics and disinfectants are hexachlorophene, cationicbisiguanides (i.e. chlorhexidine, cyclohexidine) iodine and iodophores(i.e. povidoneiodine), para-chloro-meta-xylenol, triclosan, furanmedical preparations (i.e. nitrofurantoin, nitrofurazone), methenamine,aldehydes (glutaraldehyde, formaldehyde) and alcohols. Other examples ofantiseptics and disinfectants will readily suggest themselves to thoseof ordinary skill in the art.

These antimicrobial agents can be used alone or in combination of two ormore of them. The antimicrobial agents can be dispersed throughout thematerial of the sensor and/or catheter. The amount of each antimicrobialagent used to impregnate the medical device varies to some extent, butis at least of an effective concentration to inhibit the growth ofbacterial and fungal organisms, such as staphylococci, gram-positivebacteria, gram-negative bacilli and Candida.

In some embodiments, the membrane system of the preferred embodimentspreferably include a bioactive agent, which is incorporated into atleast a portion of the membrane system, or which is incorporated intothe device and adapted to diffuse through the membrane.

There are a variety of systems and methods by which the bioactive agentis incorporated into the membrane of the preferred embodiments. In someembodiments, the bioactive agent is incorporated at the time ofmanufacture of the membrane system. For example, the bioactive agent canbe blended prior to curing the membrane system, or subsequent tomembrane system manufacture, for example, by coating, imbibing,solvent-casting, or sorption of the bioactive agent into the membranesystem. Although the bioactive agent is preferably incorporated into themembrane system, in some embodiments the bioactive agent can beadministered concurrently with, prior to, or after insertion of thedevice intravascularly, for example, by oral administration, or locally,for example, by subcutaneous injection near the implantation site. Acombination of bioactive agent incorporated in the membrane system andbioactive agent administration locally and/or systemically can bepreferred in certain embodiments.

In general, a bioactive agent can be incorporated into the membranesystem, and/or incorporated into the device and adapted to diffusetherefrom, in order to modify the tissue response of the host to themembrane. In some embodiments, the bioactive agent is incorporated onlyinto a portion of the membrane system adjacent to the sensing region ofthe device, over the entire surface of the device except over thesensing region, or any combination thereof, which can be helpful incontrolling different mechanisms and/or stages of thrombus formation. Insome alternative embodiments however, the bioactive agent isincorporated into the device proximal to the membrane system, such thatthe bioactive agent diffuses through the membrane system to the hostcirculatory system.

The bioactive agent can include a carrier matrix, wherein the matrixincludes one or more of collagen, a particulate matrix, a resorbable ornon-resorbable matrix, a controlled-release matrix, and/or a gel. Insome embodiments, the carrier matrix includes a reservoir, wherein abioactive agent is encapsulated within a microcapsule. The carriermatrix can include a system in which a bioactive agent is physicallyentrapped within a polymer network. In some embodiments, the bioactiveagent is cross-linked with the membrane system, while in others thebioactive agent is sorbed into the membrane system, for example, byadsorption, absorption, or imbibing. The bioactive agent can bedeposited in or on the membrane system, for example, by coating,filling, or solvent casting. In certain embodiments, ionic and nonionicsurfactants, detergents, micelles, emulsifiers, demulsifiers,stabilizers, aqueous and oleaginous carriers, solvents, preservatives,antioxidants, or buffering agents are used to incorporate the bioactiveagent into the membrane system. The bioactive agent can be incorporatedinto a polymer using techniques such as described above, and the polymercan be used to form the membrane system, coatings on the membranesystem, portions of the membrane system, and/or any portion of thesensor system.

The membrane system can be manufactured using techniques known in theart. The bioactive agent can be sorbed into the membrane system, forexample, by soaking the membrane system for a length of time (forexample, from about an hour or less to about a week or more, preferablyfrom about 4, 8, 12, 16, or 20 hours to about 1, 2, 3, 4, 5, or 7 days).

The bioactive agent can be blended into uncured polymer prior to formingthe membrane system. The membrane system is then cured and the bioactiveagent thereby cross-linked and/or encapsulated within the polymer thatforms the membrane system.

In yet another embodiment, microspheres are used to encapsulate thebioactive agent. The microspheres can be formed of biodegradablepolymers, most preferably synthetic polymers or natural polymers such asproteins and polysaccharides. As used herein, the term polymer is usedto refer to both to synthetic polymers and proteins. U.S. Pat. No.6,281,015, which is incorporated herein by reference in its entirety,discloses some systems and methods that can be used in conjunction withthe preferred embodiments. In general, bioactive agents can beincorporated in (1) the polymer matrix forming the microspheres, (2)microparticle(s) surrounded by the polymer which forms the microspheres,(3) a polymer core within a protein microsphere, (4) a polymer coatingaround a polymer microsphere, (5) mixed in with microspheres aggregatedinto a larger form, or (6) a combination thereof. Bioactive agents canbe incorporated as particulates or by co-dissolving the factors with thepolymer. Stabilizers can be incorporated by addition of the stabilizersto the factor solution prior to formation of the microspheres.

The bioactive agent can be incorporated into a hydrogel and coated orotherwise deposited in or on the membrane system. Some hydrogelssuitable for use in the preferred embodiments include cross-linked,hydrophilic, three-dimensional polymer networks that are highlypermeable to the bioactive agent and are triggered to release thebioactive agent based on a stimulus.

The bioactive agent can be incorporated into the membrane system bysolvent casting, wherein a solution including dissolved bioactive agentis disposed on the surface of the membrane system, after which thesolvent is removed to form a coating on the membrane surface.

The bioactive agent can be compounded into a plug of material, which isplaced within the device, such as is described in U.S. Pat. Nos.4,506,680 and 5,282,844, which are incorporated herein by reference intheir entirety. In some embodiments, it is preferred to dispose the plugbeneath a membrane system; in this way, the bioactive agent iscontrolled by diffusion through the membrane, which provides a mechanismfor sustained-release of the bioactive agent in the host.

Release of Bioactive Agents

Numerous variables can affect the pharmacokinetics of bioactive agentrelease. The bioactive agents of the preferred embodiments can beoptimized for short- and/or long-term release. In some embodiments, thebioactive agents of the preferred embodiments are designed to aid orovercome factors associated with short-term effects (e.g., acuteinflammation and/or thrombosis) of sensor insertion. In someembodiments, the bioactive agents of the preferred embodiments aredesigned to aid or overcome factors associated with long-term effects,for example, chronic inflammation or build-up of fibrotic tissue and/orplaque material. In some embodiments, the bioactive agents of thepreferred embodiments combine short- and long-term release to exploitthe benefits of both.

As used herein, “controlled,” “sustained,” or “extended” release of thefactors can be continuous or discontinuous, linear or non-linear. Thiscan be accomplished using one or more types of polymer compositions,drug loadings, selections of excipients or degradation enhancers, orother modifications, administered alone, in combination or sequentiallyto produce the desired effect.

Short-term release of the bioactive agent in the preferred embodimentsgenerally refers to release over a period of from about a few minutes orhours to about 2, 3, 4, 5, 6, or 7 days or more.

Loading of Bioactive Agents

The amount of loading of the bioactive agent into the membrane systemcan depend upon several factors. For example, the bioactive agent dosageand duration can vary with the intended use of the membrane system, forexample, the intended length of use of the device and the like;differences among patients in the effective dose of bioactive agent;location and methods of loading the bioactive agent; and release ratesassociated with bioactive agents and optionally their carrier matrix.Therefore, one skilled in the art will appreciate the variability in thelevels of loading the bioactive agent, for the reasons described above.

In some embodiments, wherein the bioactive agent is incorporated intothe membrane system without a carrier matrix, the preferred level ofloading of the bioactive agent into the membrane system can varydepending upon the nature of the bioactive agent. The level of loadingof the bioactive agent is preferably sufficiently high such that abiological effect (e.g., thrombosis prevention) is observed. Above thisthreshold, bioactive agent can be loaded into the membrane system so asto imbibe up to 100% of the solid portions, cover all accessiblesurfaces of the membrane, and/or fill up to 100% of the accessiblecavity space. Typically, the level of loading (based on the weight ofbioactive agent(s), membrane system, and other substances present) isfrom about 1 ppm or less to about 1000 ppm or more, preferably fromabout 2, 3, 4, or 5 ppm up to about 10, 25, 50, 75, 100, 200, 300, 400,500, 600, 700, 800, or 900 ppm. In certain embodiments, the level ofloading can be 1 wt. % or less up to about 50 wt. % or more, preferablyfrom about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 wt. % up to about 25,30, 35, 40, or 45 wt. %.

When the bioactive agent is incorporated into the membrane system with acarrier matrix, such as a gel, the gel concentration can be optimized,for example, loaded with one or more test loadings of the bioactiveagent. It is generally preferred that the gel contain from about 0.1 orless to about 50 wt. % or more of the bioactive agent(s), preferablyfrom about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 wt. % to about 6,7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. % or more bioactiveagent(s), more preferably from about 1, 2, or 3 wt. % to about 4 or 5wt. % of the bioactive agent(s). Substances that are not bioactive canalso be incorporated into the matrix.

Referring now to microencapsulated bioactive agents, the release of theagents from these polymeric systems generally occurs by two differentmechanisms. The bioactive agent can be released by diffusion throughaqueous filled channels generated in the dosage form by the dissolutionof the agent or by voids created by the removal of the polymer solventor a pore forming agent during the original micro-encapsulation.Alternatively, release can be enhanced due to the degradation of theencapsulating polymer. With time, the polymer erodes and generatesincreased porosity and microstructure within the device. This createsadditional pathways for release of the bioactive agent.

In some embodiments, the sensor is designed to be bioinert, e.g., by theuse of bioinert materials. Bioinert materials do not substantially causeany response from the host. As a result, cells can live adjacent to thematerial but do not form a bond with it. Bioinert materials include butare not limited to alumina, zirconia, titanium oxide or other bioinertmaterials generally used in the “catheter/catheterization” art. Whilenot wishing to be bound by theory, it is believed that inclusion of abioinert material in or on the sensor can reduce attachment of bloodcells or proteins to the sensor, thrombosis or other host reactions tothe sensor.

Sensor Electronics

The analyte sensor system has electronics, also referred to as a“computer system” that can include hardware, firmware, and/or softwarethat enable measurement and processing of data associated with analytelevels in the host. In one exemplary embodiment, the electronics includea potentiostat, a power source for providing power to the sensor, andother components useful for signal processing. In another exemplaryembodiment, the electronics include an RF module for transmitting datafrom sensor electronics to a receiver remote from the sensor. In anotherexemplary embodiment, the sensor electronics are wired to a receiver,which records the data and optionally transmits the data to a remotelocation, such as but not limited to a nurse's station, for tracking thehost's progress and to alarm the staff is a hypoglycemic episode occurs.

Various components of the electronics of the sensor system can bedisposed on or proximal to the analyte sensor, such as but not limitedto disposed on the fluid coupler 20 of the system, such as theembodiment shown in FIG. 1A. In another embodiment, wherein the sensoris integrally formed on the catheter (e.g., see FIG. 2A) and theelectronics are disposed on or proximal to the connector 218. In someembodiments, only a portion of the electronics (e.g., the potentiostat)is disposed on the device (e.g., proximal to the sensor), while theremaining electronics are disposed remotely from the device, such as ona stand or by the bedside. In a further embodiment, a portion of theelectronics can be disposed in a central location, such as a nurse'sstation.

In additional embodiments, some or all of the electronics can be inwired or wireless communication with the sensor and/or other portions ofthe electronics. For example, a potentiostat disposed on the device canbe wired to the remaining electronics (e.g., a processor, a recorder, atransmitter, a receiver, etc.), which reside on the bedside. In anotherexample, some portion of the electronics is wirelessly connected toanother portion of the electronics, such as by infrared (IR) or RF. Inone embodiment, a potentiostat resides on the fluid coupler and isconnected to a receiver by RF; accordingly, a battery, RF transmitter,and/or other minimally necessary electronics are provided with the fluidcoupler and the receiver includes an RF receiver.

Preferably, the potentiostat is operably connected to the electrode(s)(such as described above), which biases the sensor to enable measurementof a current signal indicative of the analyte concentration in the host(also referred to as the analog portion). In some embodiments, thepotentiostat includes a resistor that translates the current intovoltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

In some embodiments, the electronics include an A/D converter thatdigitizes the analog signal into a digital signal, also referred to as“counts” for processing. Accordingly, the resulting raw data stream incounts, also referred to as raw sensor data, is directly related to thecurrent measured by the potentiostat.

Typically, the electronics include a processor module that includes thecentral control unit that controls the processing of the sensor system.In some embodiments, the processor module includes a microprocessor,however a computer system other than a microprocessor can be used toprocess data as described herein, for example an ASIC can be used forsome or all of the sensor's central processing. The processor typicallyprovides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, programming for data smoothing and/or replacement of signalartifacts such as is described in U.S. Patent Publication No.US-2005-0043598-A1). The processor additionally can be used for thesystem's cache memory, for example for temporarily storing recent sensordata. In some embodiments, the processor module comprises memory storagecomponents such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM,EEPROM, rewritable ROMs, flash memory, and the like.

In some embodiments, the processor module comprises a digital filter,for example, an infinite impulse response (IIR) or finite impulseresponse (FIR) filter, configured to smooth the raw data stream from theA/D converter. Generally, digital filters are programmed to filter datasampled at a predetermined time interval (also referred to as a samplerate). In some embodiments, wherein the potentiostat is configured tomeasure the analyte at discrete time intervals, these time intervalsdetermine the sample rate of the digital filter. In some alternativeembodiments, wherein the potentiostat is configured to continuouslymeasure the analyte, for example, using a current-to-frequency converteras described above, the processor module can be programmed to request adigital value from the A/D converter at a predetermined time interval,also referred to as the acquisition time. In these alternativeembodiments, the values obtained by the processor are advantageouslyaveraged over the acquisition time due the continuity of the currentmeasurement. Accordingly, the acquisition time determines the samplerate of the digital filter. In preferred embodiments, the processormodule is configured with a programmable acquisition time, namely, thepredetermined time interval for requesting the digital value from theA/D converter is programmable by a user within the digital circuitry ofthe processor module. An acquisition time of from about 2 seconds toabout 512 seconds is preferred; however any acquisition time can beprogrammed into the processor module. A programmable acquisition time isadvantageous in optimizing noise filtration, time lag, andprocessing/battery power.

In some embodiments, the processor module is configured to build thedata packet for transmission to an outside source, for example, an RFtransmission to a receiver. Generally, the data packet comprises aplurality of bits that can include a preamble, a unique identifieridentifying the electronics unit, the receiver, or both, (e.g., sensorID code), data (e.g., raw data, filtered data, and/or an integratedvalue) and/or error detection or correction. Preferably, the data(transmission) packet has a length of from about 8 bits to about 128bits, preferably about 48 bits; however, larger or smaller packets canbe desirable in certain embodiments. The processor module can beconfigured to transmit any combination of raw and/or filtered data. Inone exemplary embodiment, the transmission packet contains a fixedpreamble, a unique ID of the electronics unit, a single five-minuteaverage (e.g., integrated) sensor data value, and a cyclic redundancycode (CRC).

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, and the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable from about 2 seconds to about 850 minutes, morepreferably from about 30 second to about 5 minutes; however, anytransmission interval can be programmable or programmed into theprocessor module. However, a variety of alternative systems and methodsfor providing a programmable transmission interval can also be employed.By providing a programmable transmission interval, data transmission canbe customized to meet a variety of design criteria (e.g., reducedbattery consumption, timeliness of reporting sensor values, etc.)

In some embodiments, the processor further performs the processing, suchas storing data, analyzing data streams, calibrating analyte sensordata, estimating analyte values, comparing estimated analyte values withtime corresponding measured analyte values, analyzing a variation ofestimated analyte values, downloading data, and controlling the userinterface by providing analyte values, prompts, messages, warnings,alarms, and the like. In such cases, the processor includes hardware andsoftware that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing. Alternatively, some portion of the data processing (such asdescribed with reference to the processor elsewhere herein) can beaccomplished at another (e.g., remote) processor and can be configuredto be in wired or wireless connection therewith.

In some embodiments, an output module, which is integral with and/oroperatively connected with the processor, includes programming forgenerating output based on the data stream received from the sensorsystem and it's processing incurred in the processor. In someembodiments, output is generated via a user interface.

In some embodiments, a user interface is provided integral with (e.g.,on the patient inserted medical device), proximal to (e.g., a receivernear the medical device including bedside or on a stand), or remote fromthe sensor electronics (e.g., at a central station such as a nurse'sstation), wherein the user interface comprises a keyboard, speaker,vibrator, backlight, liquid crystal display (LCD) screen, and one ormore buttons. The components that comprise the user interface includecontrols to allow interaction of the user with the sensor system. Thekeyboard can allow, for example, input of user information, such asmealtime, exercise, insulin administration, customized therapyrecommendations, and reference analyte values. The speaker can produce,for example, audible signals or alerts for conditions such as presentand/or estimated hyperglycemic or hypoglycemic conditions. The vibratorcan provide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight can beprovided, for example, to aid a user in reading the LCD in low lightconditions. The LCD can be provided, for example, to provide the userwith visual data output, such as is described in U.S. Patent PublicationNo. US-2005-0203360-A1. In some embodiments, the LCD is atouch-activated screen, enabling each selection by a user, for example,from a menu on the screen. The buttons can provide for toggle, menuselection, option selection, mode selection, and reset, for example. Insome alternative embodiments, a microphone can be provided to allow forvoice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, and the like. Additionally, prompts can be displayed to guidethe user through calibration or trouble-shooting of the calibration.

Additionally, data output from the output module can provide wired orwireless, one- or two-way communication between the user interface andan external device. The external device can be any device that whereininterfaces or communicates with the user interface. In some embodiments,the external device is a computer, and the system is able to downloadhistorical data for retrospective analysis by the patient or physician,for example. In some embodiments, the external device is a modem orother telecommunications station, and the system is able to send alerts,warnings, emergency messages, and the like, via telecommunication linesto another party, such as a doctor or family member. In someembodiments, the external device is an insulin pen, and the system isable to communicate therapy recommendations, such as insulin amount andtime to the insulin pen. In some embodiments, the external device is aninsulin pump, and the system is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pump.The external device can include other technology or medical devices, forexample pacemakers, implanted analyte sensor patches, other infusiondevices, telemetry devices, and the like.

The user interface, including keyboard, buttons, a microphone (notshown), and optionally the external device, can be configured to allowinput of data. Data input can be helpful in obtaining information aboutthe patient (for example, meal time, insulin administration, and thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, and the like), and downloadingsoftware updates, for example. Keyboard, buttons, touch-screen, andmicrophone are all examples of mechanisms by which a user can input datadirectly into the receiver. A server, personal computer, personaldigital assistant, insulin pump, and insulin pen are examples ofexternal devices that can provide useful information to the receiver.Other devices internal or external to the sensor that measure otheraspects of a patient's body (for example, temperature sensor,accelerometer, heart rate monitor, oxygen monitor, and the like) can beused to provide input helpful in data processing. In one embodiment, theuser interface can prompt the patient to select an activity most closelyrelated to their present activity, such as medication taken, surgicalprocedures, and the like, which can be helpful in linking to anindividual's physiological patterns, or other data processing. Inanother embodiment, a temperature sensor and/or heart rate monitor canprovide information helpful in linking activity, metabolism, and glucoseexcursions of an individual. While a few examples of data input havebeen provided here, a variety of information can be input, which can behelpful in data processing.

Algorithms

In some embodiments, calibration of an analyte sensor can be required,which includes data processing that converts sensor data signal into anestimated analyte measurement that is meaningful to a user. In general,the sensor system has a computer system (e.g., within the electronics)that receives sensor data (e.g., a data stream), including one or moretime-spaced sensor data points, measured by the sensor. The sensor datapoint(s) can be smoothed (filtered) in certain embodiments using afilter, for example, a finite impulse response (FIR) or infinite impulseresponse (IIR) filter. During the initialization of the sensor, prior toinitial calibration, the system can receive and store uncalibratedsensor data, however it can be configured to not display any data to theuser until initial calibration and, optionally, stabilization of thesensor has been established. In some embodiments, the data stream can beevaluated to determine sensor break-in (equilibration of the sensor invitro or in vivo).

In some embodiments, the system is configured to receive reference datafrom a reference analyte monitor, including one or more reference datapoints, also referred to as calibration information in some embodiments.The monitor can be of any suitable configuration. For example, in oneembodiment, the reference analyte points can comprise results from aself-monitored blood analyte test (e.g., from a finger stick test, YSI,Beckman Glucose Analyzer, and the like), such as those described in U.S.Pat. Nos. 6,045,567; 6,156,051; 6,197,040; 6,284,125; 6,413,410; and6,733,655. In one such embodiment, the user can administer aself-monitored blood analyte test to obtain an analyte value (e.g.,point) using any suitable analyte sensor, and then enter the numericanalyte value into the computer system. In another such embodiment, aself-monitored blood analyte test comprises a wired or wirelessconnection to the computer system so that the user simply initiates aconnection between the two devices, and the reference analyte data ispassed or downloaded between the self-monitored blood analyte test andthe system. In yet another such embodiment, the self-monitored analytetest is integral with the receiver so that the user simply provides ablood sample to the receiver, and the receiver runs the analyte test todetermine a reference analyte value.

In some alternative embodiments, the reference data is based on sensordata from another substantially continuous analyte sensor such asdescribed herein, or another type of suitable continuous analyte sensor.In an embodiment employing a series of two or more continuous sensors,the sensors can be employed so that they provide sensor data in discreteor overlapping periods. In such embodiments, the sensor data from onecontinuous sensor can be used to calibrate another continuous sensor, orbe used to confirm the validity of a subsequently employed continuoussensor.

In some embodiments, the sensor system is coupled to a blood analysisdevice that periodically or intermittently collects a sample of thehost's blood (e.g., through the sensor system) and measures the host'sglucose concentration. In some embodiments, the blood analysis devicecollects a blood sample from the host about every 30 minutes, everyhour, or every few hours (e.g., 2, 3, 4, 5, 6, 8, 9 or 10 hours orlonger). In other embodiments, the blood analysis device can beactivated manually (e.g., by a healthcare worker) to collect and analyzea blood sample from the host. The glucose concentration data generatedby the blood analysis device can be used by the sensor system forcalibration data. In some embodiments, the sensor system canelectronically receive (either wired or wirelessly) these calibrationdata (from the blood analysis device). In other embodiments, thesecalibration data can be entered into the sensor system (e.g., sensorsystem electronics) by hand (e.g., manually entered by a healthcareworker).

In some embodiments, the sensor system is provided with one or morecalibration solutions (e.g., glucose solutions). In some embodiments,the sensor is shipped in a calibration solution (e.g., soaked). Thesensor is activated to calibrate itself (using the calibration solutionin which it was shipped) before insertion into the host. In someembodiments, the sensor is shipped (e.g., soaked or dry) with one ormore vials of calibration solution. The sensor can be soaked (e.g.,sequentially) in the vial(s) of calibration solution; calibration datapoints collected and the sensor calibrated using those calibrationpoints, before inserting the sensor into the host.

In one exemplary embodiment, the sensor is a glucose sensor, and it isshipped soaking in a sterile 50 mg/dl glucose solution with twoaccompanying calibration solutions (e.g., 100 mg/dl and 200 mg/dlsterile glucose solutions). Prior to insertion into the host,calibration data points are collected with the sensor in the 50 mg/dl,100 mg/dl and 200 mg/dl glucose solutions respectively. The sensorsystem can be calibrated using the collected calibration data points(e.g., using regression as described in more detail elsewhere herein).In an alternative exemplary embodiment, the sensor is shipped dry (e.g.,not soaking in a solution or buffer) with at least one calibrationsolution, for calibrating the sensor prior to insertion into the host.In some embodiments, a hand held glucose monitor (e.g., SMBG devicedescribed herein) can test the calibration solutions to generatecalibration data points, which are transferred electronically ormanually to the sensor system for calibration.

In some embodiments, a data matching module, also referred to as theprocessor module, matches reference data (e.g., one or more referenceanalyte data points) with substantially time corresponding sensor data(e.g., one or more sensor data points) to provide one or more matcheddata pairs. One reference data point can be matched to one timecorresponding sensor data point to form a matched data pair.Alternatively, a plurality of reference data points can be averaged(e.g., equally or non-equally weighted average, mean-value, median, andthe like) and matched to one time corresponding sensor data point toform a matched data pair, one reference data point can be matched to aplurality of time corresponding sensor data points averaged to form amatched data pair, or a plurality of reference data points can beaveraged and matched to a plurality of time corresponding sensor datapoints averaged to form a matched data pair.

In some embodiments, a calibration set module, also referred to as thecalibration module or processor module, forms an initial calibration setfrom a set of one or more matched data pairs, which are used todetermine the relationship between the reference analyte data and thesensor analyte data. The matched data pairs, which make up the initialcalibration set, can be selected according to predetermined criteria.The criteria for the initial calibration set can be the same as, ordifferent from, the criteria for the updated calibration sets. Incertain embodiments, the number (n) of data pair(s) selected for theinitial calibration set is one. In other embodiments, n data pairs areselected for the initial calibration set wherein n is a function of thefrequency of the received reference data points. In various embodiments,two data pairs make up the initial calibration set or six data pairsmake up the initial calibration set. In an embodiment wherein asubstantially continuous analyte sensor provides reference data,numerous data points are used to provide reference data from more than 6data pairs (e.g., dozens or even hundreds of data pairs). In oneexemplary embodiment, a substantially continuous analyte sensor provides288 reference data points per day (every five minutes for twenty-fourhours), thereby providing an opportunity for a matched data pair 288times per day, for example. While specific numbers of matched data pairsare referred to in the preferred embodiments, any suitable number ofmatched data pairs per a given time period can be employed.

In some embodiments, a conversion function module, also referred to asthe conversion module or processor module, uses the calibration set tocreate a conversion function. The conversion function substantiallydefines the relationship between the reference analyte data and theanalyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=m×+b. A variety of regression orother conversion schemes can be implemented herein.

In some alternative embodiments, the sensor is a dual-electrode system.In one such dual-electrode system, a first electrode functions as ahydrogen peroxide sensor including a membrane system containingglucose-oxidase disposed thereon, which operates as described herein. Asecond electrode is a hydrogen peroxide sensor that is configuredsimilar to the first electrode, but with a modified membrane system(with the enzyme domain removed, for example). This second electrodeprovides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S. PatentPublication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=m×+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)) then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

In some alternative embodiments, the sensor system does not requireinitial and/or update calibration by the host; in these alternativeembodiments, also referred to as “zero-point calibration” embodiments,use of the sensor system without requiring a reference analytemeasurement for initial and/or update calibration is enabled. Ingeneral, the systems and methods of the preferred embodiments providefor stable and repeatable sensor manufacture, particularly when tightlycontrolled manufacturing processes are utilized. Namely, a batch ofsensors of the preferred embodiments can be designed with substantiallythe same baseline (b) and/or sensitivity (m) (+/−10%) when tested invitro. Additionally, the sensor of the preferred embodiments can bedesigned for repeatable m and b in vivo. Thus, an initial calibrationfactor (conversion function) can be programmed into the sensor (sensorelectronics and/or receiver electronics) that enables conversion of rawsensor data into calibrated sensor data solely using informationobtained prior to implantation (namely, initial calibration does notrequire a reference analyte value). Additionally, to obviate the needfor recalibration (update calibration) during the life of the sensor,the sensor is designed to minimize drift of the sensitivity and/orbaseline over time in vivo. Accordingly, the preferred embodiments canbe manufactured for zero point calibration.

In some embodiments, a sensor data transformation module, also referredto as the calibration module, conversion module, or processor module,uses the conversion function to transform sensor data into substantiallyreal-time analyte value estimates, also referred to as calibrated data,or converted sensor data, as sensor data is continuously (orintermittently) received from the sensor. For example, the sensor data,which can be provided to the receiver in “counts,” is translated in toestimate analyte value(s) in mg/dL. In other words, the offset value atany given point in time can be subtracted from the raw value (e.g., incounts) and divided by the slope to obtain the estimate analyte value:

${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some embodiments, an output module provides output to the user viathe user interface. The output is representative of the estimatedanalyte value, which is determined by converting the sensor data into ameaningful analyte value. User output can be in the form of a numericestimated analyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, medications, insulin,exercise, sensor insertion, sleep, and the like, can be obtained by thereceiver (by user input or receipt of a transmission from anotherdevice) and displayed on the graphical representation of the host'sglucose over time. It is believed that illustrating a host's life eventsmatched with a host's glucose concentration over time can be helpful ineducating the host to his or her metabolic response to the variousevents.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity measurement for usein calibrating the sensor. Furthermore, baseline and/or sensitivitymeasurements can be used to trigger events such as digital filtering ofdata or suspending display of data, all of which are described in moredetail in U.S. Patent Publication No. US-2005-0143635-A1.

In one exemplary embodiment, the sensor can be calibrated by acalibration solution. For example, after the sensor system has beeninserted into the host, a calibration solution can be injected so as topass across the electroactive surface of the analyte-measuring electrodeand the sensor calibrated thereby. For example, the saline drip can bechanged to a known IV glucose or dextrose solution (e.g., D50—a 50%dextrose solution, or D5W—a 5% dextrose solution). In one embodiment, aknown volume of D5W is infused into the host at a known rate over apredetermined period of time (e.g., 5, 10, 15 or 20 minutes, or forshorter or longer periods). During and/or after the period of infusion,the sensor measures the signal at the analyte-measuring workingelectrode. The system, knowing the specifications of the infusedcalibration solution (also referred to as a calibration information insome embodiments), can calibrate the signal to obtain host's glucoseconcentration as is appreciated by one skilled in the art. In a furtherembodiment, two or more glucose or dextrose solutions can be infused,with a corresponding signal being measured during each infusion, toprovide additional data for sensor calibration. Calibration can beperformed after the sensor has first been inserted into the host, aftera break-in time, at two or more different levels (high/low), regularly,intermittently, in response to sensor drift/shift, automatically or anyother time when calibration is required. In some alternativeembodiments, calibration can be determined during sensor break-in, suchas described in more detail elsewhere herein.

In some circumstances, catheters are flushed with saline. For example,the analyte sensor system of the preferred embodiments can be flushedwith saline prior to application of control solutions, after which apredetermined amount of glucose solution is flushed by the sensor, asdescribed above, and the sensor is calibrated there from.

In still another embodiment, a blood sample can be withdrawn from anartery or vein, and used to calibrate the sensor, for example, by usinga hand-held glucose meter, by an automatic extracorporeal glucose sensorsuch as but not limited to in conjunction with an automated bedsideclinical chemistry device, or by sending the blood sample to theclinical laboratory for glucose analysis, after which the data is input(e.g., into the electronics associated with the sensor system).

In some embodiments, the sensor can be calibrated (and/or re-calibrated)during use (after initial calibration), for example, by withdrawing oneor more blood samples (also referred to as calibration information insome embodiments), through the catheter (see FIGS. 1 and 2) and used forcalibration of the sensor, such as by measuring the glucoseconcentration of the blood sample with an additional system, such as butnot limited to a hand-held glucose meter, optical methods or additionalelectrochemical methods. Blood samples can be withdrawn manually orautomatically; additionally or alternatively, blood samples arewithdrawn at regular intervals or at selected times, for example, usingan extracorporeal blood analysis device as described herein.

In another embodiment of sensor calibration (and/or re-calibration)during use, a calibration solution (e.g., 40 mg/dL equivalent glucose,D540 or D5W) can be flushed through or by the sensor to enablecalibration of the sensor (e.g., at one time, intermittently, orcontinuously), such as described in more detail above. In theseembodiments, calibration solution can be flushed manually orautomatically through the system; additionally or alternatively,calibration solution can be flushed at regular intervals or at selectedtimes. In one exemplary embodiment, the system can be provided with adual lumen, one for saline and another for the control solution.Additionally, the system is configured to automatically switch from thesaline to control solution and perform the real-time system calibration,and then switch back to the saline solution.

Integrated Sensor System System Overview

As described above, tight control of glucose levels is critical topatient outcome in a critical care medical setting, especially fordiabetic hosts. Maintaining tight glucose control with currenttechnology poses an undue burden to medical personnel, due to timeconstraints and the extensive patient contact required. Reducing medicalstaff workload is a key component of improving patient care in thissetting. The preferred embodiments disclose systems and methods tomaintaining tight glucose control in the host while reducing and/orminimizing staff-patient interactions. Additionally, the preferredembodiments decrease testing intervals and improve sensor accuracy andreliability.

FIGS. 6 and 7 illustrate one preferred embodiment of the integratedsensor system 600 (e.g., for use at the bedside), which couples to theanalyte sensor 14 (e.g., a glucose sensor) and vascular access device 12(e.g., a catheter placed in a peripheral vein or artery) described above(see FIGS. 1A-1E), and which includes at least one fluid reservoir 602(e.g., a bag of calibration or IV hydration solution), a flow controldevice 604 (e.g., to control delivery of an infusion fluid 602 a fromthe reservoir to the host via the catheter), a local analyzer 608 and aremote analyzer 610. In some embodiments, the analyte sensor isconfigured to reside within the catheter lumen 12 a (see FIGS. 1A-1E).In some embodiments, the sensor is disposed within the catheter such thesensor does not protrude from the catheter orifice 12 b. In otherembodiments, the sensor is disposed within the catheter such that atleast a portion of the sensor protrudes from the catheter orifice. Instill other embodiments, the sensor is configured to move betweenprotruding and non-protruding dispositions. The analyte sensor andvascular access device used in the integrated sensor system 600 can beany types known in the art, such as but not limited to analyte sensorsand vascular access devices described above, in the sections entitled“Applications/Uses” and “Exemplary Sensor Configurations.” Forconvenience, the vascular access device 12 will be referred to as acatheter herein. However, one skilled in the art appreciates that othervascular access devices can be used in place of a catheter.

In some embodiments, at least one electronics module (not shown) isincluded in the local and/or remote analyzers 608, 610 respectively, forcontrolling execution of various system functions, such as but notlimited to system initiation, sensor calibration, movement of the flowcontrol device 604 from one position to another, collecting and/oranalyzing data, and the like. In preferred embodiments, the componentsand functions of the electronics module can be divided into two or moreparts, such as between the local analyzer and remote analyzer, as isdiscussed in greater detail in the sections entitled “Local Analyzer”and “Remote Analyzer.”

In some embodiments, the flow control device 604 includes one or morevalves and is configured to control fluid delivery to the host andsample take-up (e.g., drawing blood back into the catheter until atleast the sensor's electroactive surfaces are contacted by the blood).In some embodiments, the sensor 14 dwells within the lumen 12 a of thecatheter 12, as described elsewhere herein. In some embodiments, whereinan internal calibration is performed, an infusion fluid (e.g.,calibration solution 602 a) flows over the indwelling sensor 14 and isinfused into the host. Generally, analyte in the solution 602 a can bemeasured when the sensor electroactive surfaces are in contact with thesolution 602 a. In some embodiments, the measurements of the solution602 a can be used to calibrate the sensor 14. After calibration, thesystem is configured such that a sample (e.g., blood or other bodilyfluid) contacts the sensor's electroactive surfaces (e.g., by drawingblood back into the catheter). When the sample contacts theelectroactive surfaces, the sample's analyte concentration can bedetected by the sensor 14. When a sample is drawn back, the sample canthen be returned to the host. In some embodiments, the integrated sensorsystem 600 cycles between calibration (e.g., measurement of a referencecalibration solution) and measurement (e.g., of a sample, such as blood,glucose concentration). In some embodiments, the system 600 continuesoperation in this cyclical manner, until the system 600 is eitherdisconnected from the host or turned off for a period of time (e.g.,during movement of the host from one location to another). For example,in one embodiment, the system 600 cycles between the calibration andmeasurement steps from about every 30 seconds or less to about every 2hours or more. In another embodiment, the system 600 cycles between thecalibration and measurement steps of from about every 2 minutes to aboutevery 45 minutes. In still another embodiment, the system 600 cyclesbetween the calibration and measurement steps from about every 1 minuteto about every 10 minutes. In some embodiments, the user can adjust thetime between steps. In some embodiments, the user can adjust the timebetween each step. In some embodiments, the system 600 can performadditional steps, such as but not limited to a flushing step, a keepvein open step (KVO), an extended infusion step, and the like. In someembodiments, the time is dependent upon sensors that detect a referencesolution (e.g., calibration solution) and/or sample (e.g., blood) at theelectroactive surfaces.

The integrated sensor system 600 of the preferred embodiments providesseveral advantages over prior art technology. Namely, in preferredembodiments, continuous analyte monitoring is enabled. When the analyteis glucose, continuous glucose monitoring enables tight glucose control,which can lead to reduced morbidity and mortality among diabetic hosts.Additionally, the medial staff is not unduly burdened by additionalpatient interaction requirements. Advantageously, there is no net sample(e.g., blood) loss for the host, which is a critical feature in someclinical settings. For example, in a neonatal intensive care unit, thehost is extremely small and loss of even a few milliliters of blood canbe life threatening. Furthermore, returning the body fluid sample to thehost, instead of delivering to a waste container greatly reduces theaccumulation of biohazardous waste that requires special disposalprocedures. The integrated sensor system components, as well as theiruse in conjunction with an indwelling analyte sensor, are discussed ingreater detail below.

Fluids

Referring to FIGS. 6 and 7, in preferred embodiments, the integratedsensor system 600 includes at least one reservoir 602 that contains aninfusion fluid 602 a, such as but not limited to reference (e.g.,calibration), hydration and/or flushing solutions. For simplicity, theinfusion fluid 602 a will be referred to herein as a solution 602 a.However, one skilled in the art recognizes that a wide variety ofinfusible fluids can be used in the embodiments discussed herein.

In some embodiments, the reservoir 602 includes a container such as butnot limited to an IV bag. In other embodiments, the reservoir 602 caninclude two or more IV bags, or any other sterile infusion fluidcontainer. In some embodiments, the reservoir 602 is a multi-compartmentcontainer, such as but not limited to a multi-compartment IV bag. If twoor more solutions 602 a (e.g., calibration solutions, flush solutions,medication delivery solutions, etc.) are used, the solutions 602 a canbe contained in two or more IV bags or in a multi-compartment IV bag,for example. In some embodiments, it is preferred to use a singlesolution 602 a. Use of a single solution 602 a for calibration, catheterflushing and the like simplifies the system 600 by reducing thecomplexity and/or number of system 600 components required for system600 function. In some embodiments, two or more solutions 602 a arepreferred, and can be provided by a multi-compartment IV bag or two ormore separate reservoirs 602 (e.g., two or more bags, each containing adifferent solution 602 a). Advantageously, use of multiple solutions 602a can increase system functionality 600 and can improve sensor accuracy.

Any infusion fluid (e.g., solution 602 a) known in the art can be usedin conjunction with the present system 600. In some embodiments, thesolution 602 a is an analyte-containing solution that can be used as areference or standard for sensor 14 calibration (generally referred toas a calibration solution in the art). In some embodiments, a solution602 a can be used as a flushing solution, to wash a sample off thesensor 14 and out of the catheter 12. In some embodiments, two or moresolutions 602 a (e.g., having different analyte concentrations) can usedto provide two or more calibration measurements. In one exemplaryembodiment, the analyte sensor 14 is a glucose sensor, and the solution602 a contains dextrose or glucose at a concentration of from about 0mg/dl to about 400 mg/dl. In preferred embodiments, the solution 602 acontains from about 75 mg/dl to about 200 mg/dl glucose. In morepreferred embodiments, the solution 602 a contains from about 100 mg/dlto about 150 mg/dl glucose. In some embodiments, the solution 602 a isan isotonic saline solution. In some embodiments, the solution 602 acontains a sufficient concentration of an anticoagulant to substantiallyprevent blood clotting in and/or near the catheter 14. In someembodiments, the solution 602 a contains a sufficient concentration ofor antimicrobial to substantially prevent infection in and/or near thecatheter. In one exemplary embodiment, the reservoir 602 is a 500 ml bagcontaining a sterile solution 602 a including 0.9% sodium chloride inwater (e.g., normal saline), 2 IU/ml heparin and 100 mg/dl dextrose. Inanother exemplary embodiment, the reservoir 602 is a 500 ml bagcontaining heparinized saline.

In some embodiments, one, two or more solutions 602 a can be used inconjunction with the integrated sensor system 600. For example, in someembodiments, two or more calibration solutions 602 a (e.g., solutionswith different analyte concentrations) can be used. In one preferredembodiment, the analyte sensor 14 is a glucose sensor and thecalibration solution 602 a includes a glucose concentration of from 0mg/dl to about 300 mg/dl or more. In one exemplary embodiment, a singlecalibration solution 602 a (e.g., having a 100 mg/dl glucoseconcentration) can be used. In another exemplary embodiment, twocalibration solutions 602 a (e.g., having 100 mg/dl and 0 mg/dl glucoseconcentrations) can be used. In other exemplary embodiments, threecalibration (e.g., 0 mg/dl glucose, 75 mg/dl glucose and 300 mg/dlglucose) solutions 602 a can be used. In still other embodiments, morethan three calibration solutions 602 a can be used. In addition tocalibration solutions 602 a, non-calibration solutions 602 a can be usedin conjunction with the integrated sensor system 600, such as but notlimited to intravenously administered drugs, insulin, enzymes,nutritional fluids, and the like.

The solution 602 a can be provided to the user in a variety of ways,depending upon local hospital protocol and/or physician preference. Insome embodiments, the solution 602 a is supplied pre-mixed (e.g., an IVbag containing sodium chloride, dextrose and heparin), such that fluidreservoir 602 can be connected to an infusion set and infused into thehost with minimal effort. In other embodiments, one or more of thesolution components 602 a can be provided separately, such that thefinal solution 602 a is prepared at the host's bedside, at the nurse'sstation or in the hospital pharmacy, for example. In one exemplaryembodiment, the solution 602 a can be provided to the medical staff as akit including a bag of sterile solution (e.g., water) and injectablesodium chloride, dextrose and heparin aliquots of sufficient quantity toprepare the final solution 602 a. The solution 602 a can be mixed at thebedside or at a location remote from the host, and then applied to thehost and to the integrated sensor system 600. In some embodiments, thereservoir 602 is a 500 ml or 1000 ml bag containing a sterile solutionof heparinized saline and 100 mg/dl, 150 mg/dl or 200 mg/dl glucose.

In various preferred embodiments, the solutions 602 a are administeredwith standard IV administration lines, such as those commonly usedtoday, such as a sterile, single-use IV set, referred to herein astubing 606. In some embodiments, the tubing 606 can be provided with thesolution(s) 602 a. While in other embodiments, the tubing 606 can beprovided separately from the solution(s) 602 a or other systemcomponents. Additional system 600 components that can be provided withthe solution(s) 602 a include but are not limited to a sensor 14, acatheter 12, tubing 606, a local analyzer 608, wires/cables forhard-wire connections between system components, and the like.

In some embodiments, multiple solutions 602 a can be infused through amulti-lumen catheter 12, such as but not limited to a two-lumen orthree-lumen catheter. In some embodiments, the sensor 14 is disposed inone of the catheter's lumens 12 a, through which one or more calibrationsolutions 602 a can be passed, while other fluids (e.g., hydrationfluids, drugs, nutritional fluids) to be delivered to the patient areinfused through the other catheter 12 lumens 12 a (e.g., second, thirdor more lumens).

In some embodiments, the reservoir 602 is held by a support 612. Thesupport 612 can take many forms, such as an elevated support. In someembodiments, the support 612 is an IV pole, such those commonly used inmedical care facilities. In some embodiments, the reservoir 602 issuspended on the support 612, and the height of the reservoir 602 can beadjusted (e.g., raised or lowered) to modulate solution 602 a dischargefrom the reservoir 602.

In some embodiments, the reservoir 602 and solution 602 a can beprovided with one or more system 600 components, such as in a kit. Inone exemplary embodiment, a kit including the components to mix thesolution 602 a can include an analyte sensor 14 and a standard infusionset (e.g., catheter 12, cannula, IV tubing 606, etc.). In otherembodiments, a kit can include a premixed solution 602 a, with ananalyte sensor 14. In various embodiments, a kit can containinstructions for use, such as for mixing the solution 602 a and applyingit to the integrated sensor system 600. Advantageously, providing eithera pre-mixed solution 602 a or solution components with one or moresystem 600 components (e.g., sensor 14, catheter 12, tubing 606, localanalyzer 608) can increase efficiency of medical care and provide easeof use to the nursing staff

Flow Regulators

Still referring to FIGS. 6 and 7, in some embodiments, a flow regulator602 b controls the solution 602 a flow rate from the reservoir 602 tothe flow control device 604, which is described below. A variety of flowregulators can be used with the preferred embodiments, including but notlimited to pinch valves, such as rotating pinch valves and linear pinchvalves, cams and the like. In one exemplary embodiment, the flowregulator 602 b is a pinch valve, supplied with the IV set and locatedon the tubing 606 adjacent to and below the drip chamber. In someembodiments, a flow regulator 602 b controls the flow rate from thereservoir 602 to a flow control device 604, which is described in thesection entitled “Flow Control Device.” In some embodiments, a flowregulator is optional; and a flow control device 604 controls the flowrate (e.g., from the reservoir 602 to the catheter 14, describedelsewhere herein).

Flow Control Device

In preferred embodiments, the integrated sensor system 600 includes aflow control device 604. In some embodiments, the flow control device604 is configured to regulate the exposure of the sensor 14 to thesolution 602 a and to host sample (e.g., blood or other bodily fluid).In some embodiments, the flow control device 604 can include a varietyof flow regulating devices, such as but not limited to valves, cams,pumps, and the like. In one exemplary embodiment, the flow controldevice 604 includes a simple linear pinch valve. In another exemplaryembodiment, the flow control device 604 includes two or more linearpinch valves. In another exemplary embodiment, the flow control device604 includes one or more non-linear pinch valves. In another exemplaryembodiment, the flow control device 604 includes a global valve. Instill another exemplary embodiment, the flow control device 604 includesa gate valve, such as but not limited to a rising stem ornon-rising-stem valve. In another exemplary embodiment, the flow controldevice 604 includes a butterfly valve or a ball valve. In still anotherexemplary embodiment, the flow control device 604 includes a pump, suchas but not limited to volumetric infusion pumps, peristaltic pumps,piston pumps and syringe pumps. In still other exemplary embodiments,the flow control device 604 can be configured to vary the pressure atthe reservoir 602, such as but not limited to a pressure cuff around anIV bag and/or raising/lowering the reservoir adjust head pressure. Insome embodiments, the flow control device 604 includes a gravity-fedvalve. In still other embodiments, the flow control device 604 isconfigured to use flow dynamics at the catheter 12, to regulate exposureto the sensor to solution or sample, as described elsewhere herein.Although some exemplary glucose sensors are described in detail herein,the system 600 can be configured to utilize a variety of analyte sensorsincluding a variety of measurement technologies, such as enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, and the like.

Referring now to a preferred embodiment wherein the sensor is anenzyme-based sensor, it is known to those skilled in the art that therate of an enzymatic reaction is temperature dependent. Depending uponthe enzyme, temperature reductions generally slow enzymatic reactionrates; temperature increases generally increase reaction rates. Sincethe analyte sensors 14 described in the preferred embodiment hereindepend upon an enzyme (e.g., GOX) to detect the analyte (e.g., glucose)temperature changes during sensor calibration can result in artifacts onthe sensor signal. For example, if the solution 602 a temperature isreduced (relative to body temperature), the enzymatic reaction willproceed at a reduced rate (relative to the rate at body temperature),causing the solution's analyte concentration to appear artificially low,which can result in improper sensor calibration. An improperlycalibrated sensor can aberrantly measure the analyte concentration inthe sample (e.g., blood from the host). Aberrant readings of sampleanalyte concentration can lead to improper treatment decisions by themedical staff and/or the host. The effects of temperature on enzymaticreaction rates can be mathematically described using a temperaturecoefficient. Signal artifacts caused by temperature-related reductionsin enzyme reaction rate are referred to herein as temperaturecoefficient artifacts.

Generally, the host tissue in which the catheter 12 has been implantedsurrounds an in vivo portion of the catheter 12. In preferredembodiments, the flow control device 604 is configured to pass thesolution 602 a through the catheter 12 at a rate such that thesolution's temperature substantially equilibrates with the temperatureof the surrounding host tissue. In one exemplary embodiment, the flowcontrol device 604 maintains a flow rate of from about 0.5 μl/min orless to about 1.5 ml/min or more. In one preferred embodiment, the flowrate is from about 1 μl/min to about 1.0 ml/min. In one exemplarypreferred embodiment, the flow rate is from about 0.01 ml/min to about0.2 ml/min. In another exemplary preferred embodiment, the flow rate isfrom about 0.05 ml/min to about 0.1 ml/min. Advantageously, since theflow control device 604 infuses the solution 602 a at a rate sufficientto allow substantial temperature equilibration with the surroundingtissue, sensor 14 accuracy is improved and the integrated sensor system600 has substantially no temperature coefficient artifacts.

In some alternative embodiments, a faster flow rate that does not allowfor temperature equilibration is preferred. In such circumstances,measurement inaccuracies due to temperature coefficient can be generallyeliminated mathematically using b_(offset) and the calibration methodsdescribed in the section entitled “Systems and Methods for ProcessingSensor Data.”

In some embodiments, sample is taken up into the same catheter lumen 12a through which the solution 602 a is infused into the host (describedelsewhere herein). Thus, it is preferred that mixing of the sample andthe solution 602 a is prevented. Similarly, it can be advantageous todetect when the sensor 14 is in contact with undiluted sample and/orundiluted solution. In some preferred embodiments of the integratedsensor system 600, the flow control device 604 is configured tosubstantially prevent mixing of two or more fluids, such as but notlimited to the solution 602 a and a host sample (e.g., blood). Inpreferred embodiments, mixing can be substantially prevented by acombination of factors, including specific gravity and flow rate. It isknown that two solutions with different specific gravities tend not tomix, provided that the fluids are moved at a sufficiently slow rate(e.g., flow rate). Human whole blood has a specific gravity of about1.05-1.06, while an infusion solution of 5% dextrose and 0.225% NaCl hasa specific gravity of about 1.0189. Due to the difference in specificgravities, a blood sample and the solution 602 a tend to resist mixingwithin the tubing 606 when the flow rate is sufficiently slow. Inpreferred embodiments, the sample and the solution 602 a are movedwithin the catheter lumen 12 a at a rate such that substantially nomixing occurs therebetween. In some embodiments, the flow rate is fromabout 0.001 ml/min or less to about 2.0 ml/min or more. In preferredembodiments, the flow rate is from about 0.01 ml/min to about 1.0ml/min. In one exemplary preferred embodiment, the flow rate is fromabout 0.02 ml/min to about 0.35 ml/min. In another exemplary preferredembodiment, the flow rate is from about 0.0.02 ml/min to about 0.2ml/min. In yet another exemplary preferred embodiment, the flow rate isfrom about 0.085 ml/min to about 0.2 ml/min.

In preferred embodiments, the flow control device 604 can include avariety of fluid flow-regulating devices known in the art. In someembodiments, the flow control device 604 includes one or more valves,such as but not limited to linear and non-linear roller valves, linearand non-linear pinch valves, bi-directional valves (either linear ornon-linear), peristaltic rollers, cams, combinations thereof, and thelike. In some other embodiments, the flow control device 604 isconfigured to generate sufficient “head pressure” to overcome the host'sblood pressure such that the solution 602 a is infused into the host ata controlled rate; this can include elevating the fluid reservoir 602(e.g., gravity fed) and using a valve to control the fluid flow rate outof the reservoir 602 and into the host. In one exemplary embodiment, thefluid flows at a maximum rate (e.g., about 6.25 ml/hr) such that amaximum fluid volume of about 150 ml/day can be infused into the host,however ranges much higher and/or lower can be implemented with thepreferred embodiments.

In one exemplary embodiment, the flow control device 604 is a rotatingpinch valve that has first and second positions. The valve can movebetween the two positions, for example, backward and forward, andthereby move fluids in and out of the catheter, as described in thesection entitled “Flow Control Device Function.” Namely, solution 602 acan be moved from the reservoir 602, over the electroactive surfaces ofthe sensor 14 and into the host; and sample can be drawn up from thehost, to cover the electroactive surfaces of the sensor 14, and thenpushed back into the host, by movement of the valve between the firstand second positions.

In one exemplary embodiment, the flow control device includes a rotatingpinch valve as described with reference to FIGS. 8A through 8C. AlthoughFIGS. 8A to 8C describe one implementation of a rotating pinch valvethat can be implemented with the sensor system, some alternativesinclude rotating pinch valves with multiple pinch surfaces, for examplearound the circumference of the rotatable axle (FIG. 8, 804), whichenables the use of one valve for multiple infusion fluids (e.g., usingmultiple IV lines).

In some embodiments, the flow control device 604 includes one or morecams that regulate the flow rate. In one embodiment, the flow controldevice 604 includes a plurality of fixed orifices, which are opened andclosed by the cams. As the cams are rotated, the flow increases and/ordecreases in response. In one exemplary embodiment, the flow controldevice 604 includes three openings and three cams that mate with theopenings (one cam per opening); fluid can flow through each opening at agiven rate, X ml/min. Accordingly, when the cams close all threeopenings, flow is stopped. When one of the openings is opened, the fluidflows at X ml/min. If two openings are opened, fluid flows at 2×ml/min.Similarly, when the three openings are opened (e.g., by turning the camssuch that they no longer close the openings), the fluid flows at3×ml/min.

In another example, the flow control device 604 includes a plurality ofcams and an equal plurality to tubes 606 passing through the cams, suchthat each cam can pinch closed the tube 606 that passes through it. Inan exemplary embodiment, the cams are arranged such that they pinch androll the tubing 606, such that fluid is pushed into the host and sampletaken up at pre-determined rates and times. For example, the flowcontrol device 604 can include two cams, each having a tube 606 threadedtherethrough. The cams are arranged such that each cam pinches and rollsthe tubing 606 passing therethrough to push fluid into the host at oneor more rates and to take up a blood sample.

In yet another example, the flow control device includes a rotating ballvalve controlled by a motor, wherein the direction of the ball valve canbe utilized to control a variety of functions, such as flow direction ofthe fluid.

In some embodiments, an electronics module (not shown) is incorporatedinto the flow control device 604, to provide local control over flowcontrol device function; in these embodiments, the flow control devicefunction can be transmitted to the local and/or remote analyzer forprocessing. In other embodiments, a remote analyzer 610 and/orelectronics module, such as but not limited to a computer system,controls the flow control device 604. System 600 components thatregulate the flow control device 604 are discussed in greater detailelsewhere herein.

In a further embodiment, the flow control device 604 is a computercontrolled rolling pinch valve that acts on the exterior of steriletubing 606 in order to control the gravity flow of a solution 602 a froman elevated fluid reservoir 602 into the host. In preferred embodiments,the flow control device 604 is configured to pinch and roll a smallvolume of tubing 606 such that a sample of host blood is drawn up intothe catheter 12 (e.g., with a sensor 14 disposed therein) for analytemeasurement, and to then push the sample back into the host with asolution (e.g., the calibration solution 602 a). In general, the flowcontrol device 604 is configured to oscillate between drawing up a bloodsample and allowing flow of the calibration solution 602 a at apredetermined rate. In some embodiments, the flow control device 604includes at least one “hard stop” that ensures that the flow controldevice 604 does not move to a position that could endanger and/or injurethe host, such as by draining the IV bag 602 of fluid 602 a orinappropriately (e.g., excessively) withdrawing blood, for example.

Tubing Catheter

Referring again to FIGS. 6 and 7, in preferred embodiments, theintegrated sensor system 600 includes tubing 606 (e.g., sterile tubingconfigured for use in intravascular fluid infusion) and a catheter 12,to deliver the solution 602 a from the reservoir 602 to the host.Generally, the tubing 606 and catheter 12 are sterile, single usedevices generally used in medical fluid infusion, and may be referred toas an “infusion set.” An infusion set may include additional components,such as but not limited to a cannula or needle for implanting thecatheter, sterilization fluid (e.g., on a gauze pad) forcleaning/sterilizing the insertion site (e.g., the host's skin), tape,gauze, and the like. IV tubing is available in a variety of sizes andconfigurations, which find use in the preferred embodiments. Forexample, the tubing can be any size internal diameter, such as fromabout 0.5 mm to about 5 mm internal diameter. In various embodiments,the tubing can include a drip chamber and/or one or more access devices,such as but not limited to stopcocks, diaphragms and the like.

Catheters 12 are available in a variety of sizes and configurations.Catheters 12 for use in conjunction with an analyte sensor 14 aredescribed in detail, elsewhere herein. Briefly, the catheter 12 can beany single- or multi-lumen catheter having a straight or divided tubingconnector (e.g., straight-through, single shut off, double shut off,non-spill couplings, valves, T-connectors, Y-connectors, X-connectors,pinch clamps, leur locks, back-flow valves, and the like). In someembodiments, the catheter 12 is configured with an integrally formedsensor 14. In alternative embodiments, a non-integral sensor 14 isconfigured for insertion into the catheter 12 after catheter insertion.In some embodiments, the catheter 12 is a single lumen catheter that isconfigured for infusion of a fluid. In preferred embodiments, anindwelling sensor 14 is disposed within the catheter's lumen 12 a. Insome embodiments, the catheter 12 and sensor 14 are provided to a usertogether. In other embodiments, the catheter 12 and sensor 14 aresupplied separately. In an alternative embodiment, the catheter 12 is amulti-lumen catheter configured for infusion of two or more solutions.In preferred embodiments, a sensor 14 is disposed within one of thecatheter's multiple lumens 12 a. For example, a calibration solution 602a (e.g., 100 mg/dl glucose in saline) can be infused through the lumen12 a in which the sensor 14 is disposed, while a hydration fluid (e.g.,including a medication) can be infused through a second lumen.Advantageously, a dual lumen catheter 12 allows non-interrupted systemuse while other fluids are concurrently provided to the host.

In some embodiments, only the working electrode(s) of the sensor 14 aredisposed within the catheter lumen 12 a and the reference electrode isdisposed remotely from the working electrode(s). In other embodiments,the sensor 14 is configured to intermittently protrude from the catheterlumen 12 a.

Sample-Contacting Sensor

In preferred embodiments, the integrated sensor system 600 is configuredsuch that at least the sensor's electroactive surfaces can be exposed toa sample and the sample's analyte concentration can be detected.Contacting the sensor 14 with the sample can be accomplished in avariety of ways, depending upon sensor/catheter configuration. A widevariety of catheter 12 and/or sensor 14 configurations can beimplemented in the preferred embodiments, to expose the sensor'selectroactive surfaces to a biological sample. In one exemplaryembodiment, the catheter 12 is disposed in the host's peripheralvascular system, such as in a peripheral vein or artery, and a bloodsample is taken up into the catheter 12 such that the blood contacts thesensor's electroactive surfaces. In another exemplary embodiment, thecatheter 12 can be disposed in the host's central vascular system or inan extracorporeal blood flow device, such as but not limited to anarterial-venous shunt, an extravascular blood-testing apparatus, adialysis machine and the like, wherein blood samples can be taken upinto the catheter 12 such that at least the sensor's electroactivesurfaces are contacted by the drawn up blood sample.

In one exemplary embodiment, the sensor 14 is configured to residewithin the catheter lumen 12 a (e.g., not protrude from the cathetertip); and the integrated sensor system 600 is configured to draw back asample into the catheter lumen 12 a such that at least the sensor'selectroactive surfaces are contacted by the sample. In some embodiments,the sensor 14 is a small-structured sensor having a width of less thanabout 1 mm. In one preferred embodiment, the sensor has a width of lessthan about 0.4 mm. In a more preferred embodiment, the sensor has awidth of less than about 0.2 mm. In some embodiments, the catheter 12has an internal diameter of from about 0.2 mm or less to about 2.0 mm ormore, preferably from about 0.5 mm to about 1.0 mm. In some embodiments,the sensor 14 is configured such that its electroactive surfaces are ator adjacent to its tip, and the flow control device 604 is configured totake up sample into the catheter lumen 12 a until the sample covers atleast the electroactive surfaces. In some embodiments, the electroactivesurfaces are distal from the sensor's tip and sample is drawn fartherback into the catheter lumen 12 a until the sample covers theelectroactive surfaces. In some embodiments, the tip of the sensor isdisposed about 3 cm, 2 cm, or 1 cm or less from a tip of the catheter.

In some embodiments, the sample taken up into the catheter's lumen 12 acovers only a portion of the sensor's in vivo portion. In otherembodiments, the sample taken up into the catheter's lumen 12 a coversthe entire in vivo portion of the sensor 14. In some embodiments, asample volume of from about 1 μl or less to about 2 ml or more is takenup into the catheter 12 and is sufficient to cover at least theelectroactive surfaces of the sensor 14. In some preferred embodiments,the sample volume is from about 10 μl to about 1 ml. In some preferredembodiments, the sample volume is from about 20 μl to about 500 μl. Inother preferred embodiments, the sample volume is from about 25 μl toabout 150 μl. In more preferred embodiments, the sample volume is fromabout 2 μl to about 15 μl.

In preferred embodiments, the sample taken up into the catheter's lumen12 a remains within the in vivo portion of the catheter 12. For example,in some embodiments, the sample is not drawn so far back into thecatheter 12 that it enters the ex vivo portion of the catheter 12, thetubing 606 or the reservoir 602. In some embodiments, however, thesample can be drawn back as far as the catheter but not into the IVtubing. In some embodiments wherein the catheter 12 is implanted in ahost, the blood sample never leaves the host's body (e.g., a planedefined by the host's skin). In some embodiments wherein the catheter 12is implanted in an extracorporeal device, the sample does notsubstantially exit the extracorporeal device. In preferred embodiments,wherein blood is taken up into the catheter 12, the blood is returned tothe host (or extracorporeal device), which is described elsewhereherein. In preferred embodiments, the sample is blood taken up from thehost's circulatory system and into the catheter 12 disposed within thecirculatory system.

In another exemplary embodiment of the integrated sensor system, thesensor is configured to protrude from the catheter's orifice 12 b, atleast intermittently. In preferred embodiments, the sensor is configuredto protrude sufficiently far out of the catheter's lumen 12 a (e.g.,into the circulatory system proper) that the sensor's electroactivesurfaces are contacted by sample (e.g., blood). In a further embodiment,the sensor is configured to intermittently protrude from the catheterorifice 12 b, such as by moving back and forth, such that theelectroactive surfaces are alternately disposed within the catheter 12and outside of the catheter 12. In one exemplary embodiment of acatheter is implanted in a host's vein, calibration solution 602 a isprovided within the catheter 12 such that the sensor 14 is disposedwithin the catheter 12, the sensor 14 is contacted by the calibrationsolution 602 a and calibration measurements can be obtainedperiodically, when the sensor 14 (e.g., electroactive surfaces) is movedoutside of the catheter 12, the sensor 14 is contacted by blood andblood analyte measurements can be obtained.

In some embodiments of the integrated sensor system 600, the catheter 12and sensor 14 are configured to take advantage of flow dynamics withinthe host's vascular system. By taking advantage of flow dynamics, thesystem can be simplified, such that the flow control device functionsmainly to allow or block the flow of calibration solution.

FIG. 9 is a cut-away illustration of one exemplary embodiment, in whicha catheter 12 is implanted in a host's vessel 906, such as but notlimited to an artery or vein. The catheter 12 includes a sidewall 904that can be configured to include one or more holes 902 (e.g., orificesor openings configured for fluid passage, such as from the exteriorsidewall surface into the catheter lumen 12 a). The catheter 12 can beinserted into the host's vein (or artery, or an extracorporealcirculatory device) such that the catheter points either in thedirection of blood flow (antegrade) or against the direction of bloodflow (retrograde). The catheter is configured such that in an antegradeposition, blood flows into the catheter lumen 12 a via the holes 902 andthen out of the catheter orifice 12 b. In a retrograde position, bloodenters the catheter lumen 12 a via the catheter orifice 12 b and flowsout of the lumen through the holes 902. In some embodiments, the sensor14 can be disposed within the catheter lumen 12 a such that bloodflowing between the holes 902 and the orifice 12 b contacts at least thesensor's electroactive surfaces. In some embodiments, the sensor 14 isconfigured to be substantially immobile within the lumen 12 a, while inother embodiments the sensor 14 is configured to be substantiallymoveable within the lumen 12 a, as described in more detail elsewhereherein.

Generally, the holes 902 can be placed in any location on the catheter'ssidewall 904. In some embodiments, the holes 902 can be located near oradjacent to the catheter orifice 12 a. In other embodiments, the holes902 can be placed remotely from the catheter orifice 12 a. The size,shape and number of holes 902 can be selected to optimize the samplevolume and flow rate through the catheter lumen 12 a. For example, insome embodiments, the holes 902 are round, ellipsoid, rectangular,triangular, star-shaped, X-shaped, slits, combinations thereof,variations there of, and the like. Similarly, in some embodiments, thecatheter 12 can have from 1 to about 50 or more holes 902. In otherembodiments, the catheter can have from 2 to about 10 or more holes 902.

In some alternative embodiments, the catheter includes at least one sizewall orifice in place of an end tip orifice, which allows selectiveexposure of the sensor to the host's biological sample there through. Avariety of alternative catheter configurations are contemplated inconjunction with the preferred embodiments.

In one exemplary embodiment of the integrated sensor system 600, theflow control device 604 is configured to intermittently block theinfusion of solution 602 a through the catheter 12, which is configuredwith side holes 902 as described above. Additionally, the analyte sensoris disposed within the catheter lumen 12 a such that sample passingbetween the side holes 902 and the catheter orifice 12 b bathes thesensor's electroactive surfaces, during which time an analytemeasurement can be obtained. When the flow control device 604 does notblock infusion, the solution 602 a contacts the sensor's electroactivesurfaces; and calibration measurements can be taken.

In some embodiments, a solution 602 a can be infused into the catheter12 at a rate such that the flow of sample between the holes 902 and theorifice 12 b is substantially blocked and at least the electroactivesurfaces are bathed in the solution 602 a (e.g., undiluted solution). Inpreferred embodiments, the sensor 14 can be calibrated while it isbathed in the undiluted solution 602 a.

In preferred embodiments, the sensor 14 is a small-structured sensorwith at least one electrode, such as a working electrode, as describedelsewhere herein. In some embodiments, the sensor 14 has two or moreelectrodes, such as but not limited to working, reference and counterelectrodes. In some embodiments, the sensor 14 includes a referenceelectrode disposed remotely from the working electrode, as discussedelsewhere herein. In some embodiments, the sensor 14 includes two ormore electrodes that are separated by an insulator, such as described inU.S. Patent Publication No. US-2007-0027385-A1, to Brister et al, hereinincorporated by reference in its entirety. In preferred embodiments, theelectrode is a fine wire, such as but not limited to a wire formed fromplatinum, iridium, platinum-iridium, palladium, gold, silver, silverchloride, carbon, graphite, gold, conductive polymers, alloys and thelike. In some exemplary embodiments, the sensor 14 includes one or moreelectrodes formed from a fine wire with a diameter of from about 0.001or less to about 0.010 inches or more. Although the electrodes can byformed by a variety of manufacturing techniques (bulk metal processing,deposition of metal onto a substrate, and the like), it can beadvantageous to form the electrodes from plated wire (e.g., platinum onsteel wire) or bulk metal (e.g., platinum wire). It is believed thatelectrodes formed from bulk metal wire provide superior performance(e.g., in contrast to deposited electrodes), including increasedstability of assay, simplified manufacturability, resistance tocontamination (e.g., which can be introduced in deposition processes),and improved surface reaction (e.g., due to purity of material) withoutpeeling or delamination.

In some embodiments, one or more electrodes are disposed on a support,such as but not limited to a planar support of glass, polyimide,polyester and the like. In some exemplary embodiments, the electrodesinclude conductive inks and/or pastes including gold, platinum,palladium, chromium, copper, aluminum, pyrolitic carbon, compositematerial (e.g., metal-polymer blend), nickel, zinc, titanium, or analloy, such as cobalt-nickel-chromium, or titanium-aluminum-vanadium,and are applied to the support using known techniques, such as but notlimited to screen-printing and plating. Additional description can befound in U.S. Pat. No. 7,153,265, US patent publication 2006-0293576, USpatent publication 2006-0253085, U.S. Pat. No. 7,003,340, and U.S. Pat.No. 6,261,440, all of which are incorporated in their entirety byreference herein.

In some embodiments, an optional redundant sensor can be disposed withinthe catheter lumen, in addition to the sensor 14 described elsewhereherein. In one exemplary embodiment, a sensor 14 and a redundant sensorare disposed within the lumen of a sensor implanted in a host'speripheral vein, such that the electroactive surfaces of the sensor 14are more proximal to the catheter orifice 12 b than the electroactivesurfaces of the redundant sensor; wherein blood is taken up into thelumen 12 a such that the electroactive surfaces of both the sensor 14and the redundant sensor are contact by the blood; such that analyte canbe detected by both the sensor 14 and the redundant sensor and theredundant sensor measurements are used by the system 600 to confirm thesensor's 14 measurements. In a further embodiment, both the sensor 14and the redundant sensor are intermittently concurrently contacted bythe solution 602 a such that both the sensor 14 and the redundant sensorcan take calibration measurements of the solution 602 a, wherein thecalibration measurements of the redundant sensor are at least used toconfirm the calibration measurements of the sensor 14. In anotherembodiment, the calibration measurements from both the sensor 14 and theredundant sensor are used to calibrate the sensor 14.

Local Analyzer

Referring to FIGS. 6 and 7, in some embodiments, the integrated sensorsystem 600 includes a local analyzer 608 configured to operably connectto a remote analyzer 610. In some embodiments, the local analyzer 608 isproximal to an analyte sensor 14 and the remote analyzer 610 isconfigured to operably connect to the local analyzer. However,alternative configurations are possible, such as the analyte sensor 14can be operably connected to both the local and remote analyzers 608,610 respectively. The remote analyzer 610 of the preferred embodimentsis discussed below. In various embodiments, one or more functions of thelocal analyzer 608 can be transferred to the remote analyzer, as isappreciated by one skilled in the art. Likewise, in some embodiments,one or more functions of the remote analyzer 610 can be incorporatedinto the local analyzer 608. In further embodiments, functions of thelocal and/or remote analyzers 608, 610 can be disposed in one, two,three or more physical bodies (e.g., separate housings), depending uponthe integrated sensor system 600 configuration and/or componentcombinations. For example, in one embodiment, the local analyzer 608includes a potentiostat, a power source (e.g., battery or connection toan electrical source), and data storage; and the local analyzer 608 isconfigured such that the potentiostat is disposed on the sensor's fluidcoupler 20 and the remaining local analyzer 608 components are disposedelsewhere between the local analyzer 608 and the remote analyzer 610(e.g., connected by wiring).

Operable connections between the local and remote analyzers 608, 610 andthe analyte sensor 14 can be accomplished by a hard wire (e.g., USB,serial), RF communication, IR communication, and the like. In someembodiments, operable connections include a connector known in the art,such as but not limited to mating plug and socket units, screwconnectors, clips and the like. In some embodiments, the connectors areseparable. In other embodiments, the connectors are inseparable. In someembodiments, the connectors include a lock, to prevent inadvertentdisconnection. In some embodiments, the local analyzer can be isolatedfrom the remote analyzer by an isolation transformer.

In some embodiments, the local analyzer 608 is operably connected to thesensor 14 (e.g., the sensor electrode(s)), such as by a wire connection.A detailed description of electronic components and configurations isdescribed elsewhere herein, for example, in the section entitled “SensorElectronics.” In some embodiments, the local analyzer 608 is disposed onor adjacent to the sensor, such as on the sensor fluid coupler 20. Inone exemplary embodiment, the sensor's fluid coupler 20 includes a localanalyzer housing that includes at least a potentiostat. In someembodiments, the housing can include a battery and electronics, suchthat the sensor 14 can be powered, and data can be collected and/ortransmitted to additional system electronics (e.g., electronics unitsdisposed remotely from the sensor, such as on the host's arm, on thehost's bed and in the remote analyzer, and the like). In someembodiments, the local analyzer 608 includes a small housing that isconnected to the sensor 14 via a short wire (e.g., from about 1 cm orless to about 10 cm or more) and is taped to the host's skin, such asadjacent to the catheter's insertion site on the host's arm or hand. Ina further embodiment, the local analyzer 608 includes a connector, suchas but not limited to a “plug” configured to mate with a “socket” wiredto the sensor 14, such that an electrical connection can be made betweenthe local analyzer 608 and the sensor 14. In another embodiment, thesensor 14 includes a cable having a plug configured to connection to thelocal analyzer 608 via a socket. In still another embodiment, both thesensor 14 and the local analyzer 608 include cables configured to matewith each other via a plug and socket mechanism. Advantageously, adetachable configuration allows catheter/sensor insertion without acumbersome connection to the local analyzer 608 as well as re-use of thelocal analyzer 608. In an alternative exemplary embodiment, the localanalyzer 608 is permanently connected to the sensor 14 and cannot bedisconnected therefrom; a single use, permanently connectedconfiguration can simplify application to the host, can reduce thepossibility of cross-contamination between hosts, does not requirecleaning and/or sterilization between hosts, and can reduce operatorerror during application to the host.

In preferred embodiments, the local analyzer 608 includes at least theminimal electronic components and/or programming required to energizethe sensor 14 and collect data therefrom, such as but not limited to apotentiostat. However, in some embodiments, the local analyzer 608includes additional electronic components that can be programmed toanalyze one or more components of the collected raw signal, or to storedata, calibration information, a patient ID and the like. In oneexemplary embodiment, the local analyzer 608 includes a potentiostat anda battery back up. The battery back up can maintain a potential on thesensor and store data (calibration and/or collected host data) for briefperiods of time when the electronics can be disconnected, such as whenthe host is moved from one location to another. In one exemplaryembodiment, the local analyzer 608 is disposed on or adjacent to thesensor 14 and is configured such that the host can be connected to afirst remote analyzer 610 at one station, and then disconnected from thefirst remote analyzer 610, moved to a new location and connected to asecond remote analyzer 610 at the new location, and the local analyzer608 retains sufficient data that the system 600 functions substantiallywithout initialization or substantial delay upon connection to the new(second) remote analyzer 610. In another example, the host can bedisconnected from the first remote analyzer 610, taken to anotherlocation for a procedure (e.g., for surgery, imaging, and the like) andthen reconnected to the first remote analyzer 610 upon return to theoriginal location without substantial loss of system 600 function uponreconnection.

In some embodiments, the local analyzer 608 includes two or more parts,such that only the potentiostat is disposed on or adjacent to the sensor14 (e.g., sensor fluid coupler 20) or the catheter (e.g., catheterconnector 18); other portions of the local analyzer 608 can be disposedremotely from the host, such as in a separate housing wired to thesensor and to the remote analyzer. In one exemplary embodiment, the twoparts of the local analyzer 608 can be separated (e.g., unplugged) suchthat the host can be moved and the local analyzer 608 portion that isattached to the host goes with the host while the remaining portionstays with the remote analyzer 610.

In still other embodiments, all sensor electronics components aredisposed remotely from the host, such as in the remote analyzer 610. Forexample, the sensor 14 can include an appropriate connector, plug and/orwiring to connect the sensor 14 to the remote analyzer 610, which powersthe sensor 14, collects raw data from the sensor 14, calibrates thesensor 14, analyzes and presents the data, and the like. In one example,the sensor 14 includes a cable of sufficient length to permit pluggingthe sensor 14 into a remote analyzer 610 disposed at the host's bedside.

In still other embodiments, the local analyzer 608 can be incorporatedinto the remote analyzer 610, such as housed in the same body as theremote analyzer 610, for example. In one exemplary embodiment, both thelocal and remote analyzers 608, 610 are disposed in a housing attachedto a support 612 (e.g., connected to an IV pole, placed on a bedsidetable, connected to the wall, clamped to the head of the host's bed) andconnected to the analyte sensor via a wire or cable. In someembodiments, the cables/wires (e.g., for connecting the sensor to thelocal analyzer and/or the remote analyzer, and/or connecting the localanalyzer to the remote analyzer) can be provided in the IV tubing set.

Remote Analyzer

As discussed in the section entitled “Local Analyzer,” the integratedsensor system 600 includes a remote analyzer 610. In preferredembodiment, the remote analyzer 610 is configured to at leastcommunicate with the local analyzer 608 and can be configured to controlthe flow control device 604 described in the sections entitled “FlowControl Device,” and “Flow Control Device Function.” Generally, theremote analyzer 610 is powered from a standard 120VAC wall circuit orother suitable power source, for example. In some embodiments, theremote analyzer 610 is disposed at the host's bedside and can beconfigured to be disposed on a support 612, such as but not limited to,mounted a mobile IV drip pole, attached to the wall, clamped to thehost's bed, or sitting on a table or other nearby structure.

In preferred embodiments, the remote analyzer 610 includes a display,such as but not limited to a printout, an LED display, a monitor, atouch-screen monitor and the like. In some embodiments, the remoteanalyzer 610 includes both a hard copy display, such as a printerconfigured to print collected data, and a monitor. In some embodiments,the remote analyzer 610 is a programmable touch-screen panel PCconfigured to have different “screens” and “buttons” for control ofsystem components (e.g., the sensor 14, the flow control device 604,etc.) and to display data, such as but not limited to hostidentification and condition, host food intake, medication schedules anddosage information, sensor identification, raw data, processed data,calibration information, and the like, such as in tables and/or graphs.In further preferred embodiments, the remote analyzer 610 is configuredto be programmed, such that the operator can initiate system functionssuch as IV fluid line priming, starting and/or stopping the flow controldevice 604, select among two or more solutions (e.g., between glucoseconcentrations), select the mode of data delivery (e.g., printer oron-screen), send data to a central location (e.g., the nurse's stationor medical records), set alarms (e.g., for low and high glucose), andthe like.

In some embodiments, the system 600 is configured to integrate with(e.g., be used in conjunction with) third party medical devices, such asbut not limited to a pulse-oxygen meter, a blood pressure meter, a bloodchemistry machine, and the like. In such embodiments, the local and/orremote analyzers 608, 610 can be configured to communicate with thethird party medical devices, such as but not limited to a patientmonitor.

Flow Control Device Function

In some embodiments, the remote analyzer 610 controls the function ofthe flow control device 604. In some embodiments, the flow controldevice includes electronics configured to control the flow controldevice. The flow control device 604 can be configured to perform anumber of steps of operation, which are discussed below. Depending uponthe system configuration and physician preferences, in some embodiments,one or more of the steps can be performed. In some embodiments, all ofthe steps are performed. In some embodiments, the steps of operation canbe performed in the order in which they are presented herein. In otherembodiments, the order of steps of operation can be varied (e.g.,repeated, omitted, rearranged), depending upon various parameters, suchas but not limited to the calibration solution 602 a selected, theparticular infusion set selected, catheter 12 size, host condition,analyte of interest, type of sample and location of sample collection,integration with third party devices, additional infusion of fluids andthe like.

FIGS. 8A through 8C are schematic illustrations of a flow control devicein one exemplary embodiment, including its relative movement/positionsand the consequential effect on the flow of fluids through thesensor/catheter inserted in a host. In general, steps performed by theflow control device 604, include the steps of: contacting the sensor 14with calibration solution 602 a (including sensor calibration) andcontacting the sensor with a biological sample to be measured. In someembodiments, additional steps can be taken, such as but not limited tokeep a vein open (KVO) step and a wash step. In the exemplary embodimentpresented in FIGS. 8A though 8C, the flow control device 604 is a rollervalve configured to move between at least two positions, 810 and 812,respectively. Movement of the flow control device 604 between positions810 and 812 effectively concurrently moves the pinch point 808 (e.g.,the point at which tubing 606 is pinched) between positions 810 and 812.Additional flow control device positions are discussed below.

The top of FIGS. 8A through 8C are schematic drawings illustratingpositions of the flow control device 604. The bottom of FIGS. 8A through8C, are a cut-away views of an implanted catheter 12, including anindwelling sensor 14, illustrating the corresponding activity at theimplantation site, in response to movements of the flow control device604. For simplicity, for purposes of discussion only, it is assumed thatthe catheter 12 is implanted in a host's vein, that the sensor 12 doesnot protrude from the catheter's orifice 12 b and that the catheter 14does not include side holes 902. However, one skilled in the artappreciates that the catheter 14 could be implanted into any vessel ofthe host or into a variety of extracorporeal devices discussed elsewhereherein.

Step One: Contacting Sensor with Calibration Solution

In general, the system is configured to allow a calibration solution tocontact the sensor using a flow control device such as a pump, valve orthe like. In some embodiments, such as shown in FIGS. 8A through 8C, theflow control device 604 is a valve configured with a first structure 802and a second structure 806. For convenience, the first structure 802 isdepicted as a roller connected to a rotatable axle 804, however any flowcontrol device such as described in the section entitled “Flow ControlDevice,” can be configured to utilize the concepts and/or functionsdescribed herein. In general, when the flow control device is a valve,the valve is configured to allow no flow, free flow and/or metered flowthrough movement of the valve between one or more discreet positions.

In the embodiment shown in FIGS. 8A through 8C, the flow control device604 is configured such that a tube 606 threaded between the first andsecond structures 802, 806 (e.g., between the roller and the surfaceagainst which the roller presses) is compressed substantially closed.For convenience, the compressed location on the tubing is referred toherein as the “pinch point” 808. In some embodiments, the flow controldevice 604 is configured such that the pinch point is moved along thetubing, either closer to or farther from the host. As the pinch point808 is moved closer to the host, the tube 606 is progressivelycompressed, causing fluid (e.g., solution 602) to be pushed into thehost's vascular system (see the corresponding illustration of the sensorwithin the host's vessel at the bottom of FIG. 8A), at the catheter 12implantation site. Conversely, as the pinch point 808 is moved away fromthe host, the portion of tubing 606 on the host side of the pinch point808 progressively expands, causing sample (e.g., blood) to be drawn upinto the catheter lumen 12 a. In an alternative embodiment, the flowcontrol device 604 is configured such that the pinch point issubstantially stationary and the first and second structures selectivelycompress the tubing at the pinch point (e.g., the tube 606 is eitherpinched fully closed or is fully open), which either stops or allows theflow of solution 602 a.

In the exemplary embodiment shown in FIG. 8A (bottom), the catheter 12is implanted in the host's vein 906 (or artery), as described elsewhereherein. A sensor 14 is disposed with the catheter 12. The catheter 12 isfluidly connected to a first end of tubing 606 that delivers thesolution 602 a to the catheter 12. The solution 602 a can move out ofthe catheter 12 and a sample of blood 814 can move in and out of thecatheter 12, via the catheter's orifice 12 b. In some alternativeembodiments, the catheter 12 includes optional sidewall holes 902 (seeFIG. 9, described elsewhere herein) and the solution 602 a and blood canmove in and out of the catheter 12 via the sidewall holes 902 and thecatheter orifice 12 b. In some alternative embodiments, the sensor isconfigured to move in and out of the catheter. In some embodiments, thecatheter orifice 12 b is disposed in the sidewall 904 (e.g., near thecatheter's tip) instead of at the tip. Tubing 606 is fluidly connectedto the reservoir 602 on a second end (see FIGS. 6 and 7).

Referring now to a calibration phase to be performed by the exemplaryvalve of FIG. 8A, in preferred embodiments, the flow control device 604is configured to perform a step of contacting the sensor 14 withsolution 602 a, wherein the flow control device 604 moves from position810 to position 812 (e.g., forward, toward the host/catheter). When theflow control device 604 moves from position 810 to position 812, thepinch point 808 is moved from position 810 to position 812. As the pinchpoint 808 is moved from position 810 to position 812, a first volume ofthe calibration solution 602 a is pushed through the tubing 606, towardthe catheter 12.

Referring again to the bottom of FIG. 8A, a second volume of thesolution 602 a, which is substantially equal to the first volume, ispushed into the host's vein 906, in response to the first volume ofsolution 602 a moving toward the host. As the second volume of solution602 a is pushed through the catheter 12 and into the host's vein thesecond volume contacts (e.g., bathes) the analyte sensor 14, includingthe analyte sensor's electroactive surfaces. In some embodiments, thevolume (e.g., the first and second volumes of fluid) moved is from about3 μl or less to about 1 ml or more. In some preferred embodiments, thevolume is from about 10 μl to about 500 μl, or more preferably fromabout 15 μl to about 50 μl. In general, the volume of fluid pushedthrough the catheter in a particular phase (e.g., calibration phase) isdependent upon the timing of the phase. For example, if a long phase,such as a 20 minute calibration phase (e.g., as compared to a shorter 5minute phase) were selected, the volume of fluid pushed during the longphase would be 4× greater than the volume of fluid pushed during theshorter phase. Accordingly, one skilled in the art appreciates that theabove described ranges of fluids infusion can be increased and/ordecreased simply be increasing or decreasing the measurement phaseand/or intervals (i.e., timing). In preferred embodiments, the fluid ismoved at a flow rate that is sufficiently slow that the calibrationsolution's temperature substantially equilibrates with the temperatureof the tissue surrounding the in vivo portion of the catheter and/ortemperature of bodily fluid (e.g., blood). In preferred embodiments, theflow rate is from about 0.25 μl/min or less to about 10.0 ml/min ormore. In one exemplary embodiment, the flow control device 604 maintainsa flow rate from about 0.5 μl/min or less to about 1.5 ml/min or more.In one preferred exemplary embodiment, the flow rate is from about 1μl/min to about 1.0 ml/min. In one exemplary preferred embodiment, theflow rate is from about 0.01 ml/min to about 0.2 ml/min. In anotherexemplary preferred embodiment, the flow rate is from about 0.05 ml/minto about 0.1 ml/min.

In some embodiments, the system is configured such that the speed of themovement between the first and second discreet positions is regulated ormetered to control the flow rate of the fluid through the catheter. Insome embodiments, the system is configured such that the time ofmovement between the first and second discreet positions is from about0.25 to 30 seconds, preferably from about 0.5 to 10 seconds. In someembodiments, the system is configured such that an amount of pinch ofthe tubing regulates the flow rate of the fluid through the catheter. Insome embodiments, the fluid flow is regulated through a combination ofmetering and/or pinching techniques, for example. Depending on the typeof flow control device (e.g., valve), a variety of methods of meteringand/or regulating the flow rate can be implemented as is appreciated byone skilled in the art.

Preferably, the sensor is configured to measure a signal associated withthe solution (e.g., analyte concentration) during the movement of theflow control device from position 810 to position 812 and/or duringcontact of the sensor 14 with the solution 602 a. Electronics, such asan electronic module included in either the local or remote analyzer608, 610 controls signal measurement and processing, such as describedin more detail elsewhere herein.

In general, a calibration measurement can be taken at any time duringthe flow control device 604 movement from position 810 to position 812,and including a stationary (stagnant) time there after. In someembodiments, one or more calibration measurements are taken at thebeginning of the flow control device 604 movement from position 810 toposition 812. In other embodiments, one or more calibration measurementsare taken at some time in the middle of the flow control device 604movement from position 810 to position 812. In some embodiments, one ormore calibration measurements are taken near the completion of the flowcontrol device 604 movement from position 810 to position 812. In someembodiments, one or more calibration measurements are taken aftercompletion of the flow control device 604 movement from position 810 toposition 812. In still other embodiments, the flow control device ispositioned such that fluid can flow followed by positioning the flowcontrol device such that there is no fluid flow (e.g., 0 ml/min) duringthe calibration measurement. In preferred embodiments, one or morecalibration measurements are taken when the temperature of the solution602 a has substantially equilibrated with the temperature of the tissuesurrounding the in vivo portion of the implanted catheter 12. Processingof calibration measurements and sensor calibration are describedelsewhere herein.

Step Two: Sample Collection and Measurement

In general, the system is configured to allow a sample (e.g., blood) tocontact the sensor using the flow control device. Referring now to thetop of FIG. 8B, the flow control device 604 is configured to draw back(or take-in) a sample (e.g., blood) from the host. For example, tocollect a sample, the flow control device 604 reverses and movesbackward (e.g., away from the host/catheter), from position 812 toposition 810, thereby causing the pinch point 808 to move away from thehost. As the pinch point is moved from position 812 to position 810, thetube 606 (on the host side of the pinch point 808) expands (e.g., thetube volume increases).

Referring now to the bottom of FIG. 8B, as the tube volume increases, asmall, temporary vacuum is created, causing sample 814 (e.g., blood) tobe taken up into the catheter lumen 12 a. In some embodiments, the flowcontrol device 604 is configured to take up a sufficient volume ofsample 814 such that at least the sensor's electroactive surfaces arecontacted by the sample 814. In some embodiments, a sample volume offrom about 1 μl or less to about 2 ml or more is taken up into thecatheter 12 and is sufficient to cover at least the electroactivesurfaces of the sensor 14. In some preferred embodiments, the samplevolume is from about 10 μl to about 1 ml. In some preferred embodiments,the sample volume is from about 20 μl to about 500 μl. In otherpreferred embodiments, the sample volume is from about 25 μl to about150 μl. In more preferred embodiments, the sample volume is from about 2μl to about 15 μl.

In some embodiments, the sample taken up into the catheter is taken upsubstantially no farther than the skin (or a plane defined by the skinof the patient). In some embodiments, the sample is taken up into thecatheter substantially no farther than the catheter's inner lumen (e.g.,substantially not into the IV tubing.)

In some embodiments, the rate of sample take-up is sufficiently slowthat the temperature of the sample substantially equilibrates with thetemperature of the surrounding tissue. Additionally, in someembodiments, the rate of sample take-up is sufficiently slow such thatsubstantially no mixing of the sample 814 and solution 602 a occurs. Insome embodiments, the flow rate is from about 0.001 ml/min or less toabout 2.0 ml/min or more. In preferred embodiments, the flow rate isfrom about 0.01 ml/min to about 1.0 ml/min. In one exemplary preferredembodiment, the flow rate is from about 0.02 ml/min to about 0.35ml/min. In another exemplary preferred embodiment, the flow rate is fromabout 0.0.02 ml/min to about 0.2 ml/min. In yet another exemplarypreferred embodiment, the flow rate is from about 0.085 ml/min to about0.2 ml/min.

As described above, in some embodiments, the system is configured suchthat the speed of the movement between the first and second discreetpositions is regulated or metered to control the flow rate of the fluidthrough the catheter. In some embodiments, the system is configured suchthat the time of movement between the first and second discreetpositions is from about 0.25 to 30 seconds, preferably from about 0.5 to10 seconds. In some embodiments, the system is configured such that thetime of movement between the first and second discreet positions is fromabout 0.25 to 30 seconds, preferably from about 0.5 to 10 seconds. Insome embodiments, the system is configured such that an amount of pinchof the tubing regulates the flow rate of the fluid through the catheter.In some embodiments, regulate the fluid flow through a combination ofmetering and/or pinching techniques, for example. Depending on the typeof flow control device (e.g., valve), a variety of methods of meteringand/or regulating the flow rate can be implemented as is appreciated byone skilled in the art.

Measurements of sample analyte concentration can be taken while theelectroactive surfaces are in contact with the sample 814. Anelectronics module included in the local and/or remote analyzer 608, 610controls sample analyte measurement, as described elsewhere herein. Insome embodiments, one sample measurement is taken. In some embodiments,a plurality of sample measurements are taken, such as from about 2 toabout 50 or more measurements and/or at a sample rate of between about 1measurement per second and about 1 measurement per minute. In someembodiments, the rate is from about 1 measurement per 2 seconds to about1 measurement per 30 seconds. In preferred embodiments, samplemeasurements are taken substantially continuously, such as but notlimited to substantially intermittently, as described elsewhere herein.

Optional Step: Flush

In some exemplary embodiments, the flow control device 604 is configuredto perform one or more steps, in addition to steps one and two,described above. A flush step, during which the sensor 14 and/orcatheter 12 are substantially washed and/or cleaned of host sample, isone such optional step.

Referring now to the top of FIG. 8C, the exemplary flow control device604 performs a flush step by moving forward from position 810 (e.g.,toward the host/catheter), past position 812 (e.g., around and over thetop of structure 804) and back to position 810. For convenience, themovement illustrated by an arrow in the top of FIG. 8C is referred toherein as the “flush movement.”

Referring now to the bottom of FIG. 8C, the flush movement pushesforward a volume of solution 602 a (e.g., a third volume) that pushesthe collected blood sample 814 into the host. In some embodiments, thethird volume of solution 602 a is substantially equal to the first andsecond volumes described above. In some embodiments, the flush movementis repeated at least one time. In some embodiments, the flush movementis repeated two, three or more times. With the exception of the firstflush movement, which pushes the sample 814 back into the host, eachrepeat of the flush movement pushes a volume of solution 602 a into thehost, for example. In some embodiments, the flush movement pushes thethird volume of solution 602 a into the host at a rate of from about0.25 μl/min or less to about 10.0 ml/min or more. In preferredembodiments the flush movement pushes the third volume of solution intothe host at a rate of from about 1.0 μl/min to about 1.0 ml/min. Inalternative embodiments, the flow control device 604 is moved to a fullyopened position (e.g., no pinch) and the flow regulator 602 b is set ata setting that allows more solution (e.g., an increased volume and/or ata faster rate) to infuse into the host than during the calibration phase(e.g., step one, above). In preferred embodiments, the flush movementwashes enough blood off of the analyte sensor's electroactive surfacesthat the sensor 14 can measure the solution 602 a substantially withoutany interference by any remaining blood. In some embodiments, the flushstep is incorporated into step one, above.

Generally, the solution 602 a is flushed through the catheter 12, toensure that a sufficient amount of the sample has been removed from thesensor 14 and the catheter lumen 12 a, such that a calibrationmeasurement can be taken. However, in some embodiments, sample iscollected, measured and flushed out, followed by collection of the nextsample, substantially without sensor calibration; the flush step can beexecuted between samples to ensure that the sample being analyzed issubstantially uncontaminated by the previous sample. In someembodiments, a relatively extended flush is used, while in otherembodiments the flush is just long enough to ensure no blood remains.

In some embodiments, the effectiveness of the flushing movement isdependent upon the solution 602 a composition (e.g., concentrations ofsodium chloride, glucose/dextrose, anticoagulant, etc.). Accordingly,the amount of solution 602 a required to ensure that substantially nosample remains in the catheter 12 and/or on the sensor 14 can depend onthe solution 602 a composition. For example, relatively more flushmovements may be required to completely remove all of the sample when anon-heparinized solutions is selected than when a heparinized solutionis selected. In some embodiments, the effectiveness of the flushingmovement is also dependent upon the flush flow rate. For example, arelatively faster flow rate can be more effective in removing samplefrom the sensor than a slower flow rate, while a slower flow rate canmore effectively move a larger volume of fluid. Accordingly, in someembodiments, the number of flush movements selected is dependent uponthe calibration solution and flow rate selected. In some embodiments,the flush step flow rate is from about 0.25 μl/min or less to about 10.0ml/min or more, and last for from about 10 seconds or less to about 3minutes or more. In one exemplary embodiment, about 0.33 ml of solution602 a is flushed at a rate of about 1.0 ml/min, which takes about 20seconds.

In some embodiments, the flush step returns the sample 814 (e.g., blood)to the host, such that the host experiences substantially no net sampleloss. Further more, the flush movement washes the sensor 14 and catheterlumen 12 a of a sufficient amount of sample, such that an accuratecalibration measurement (e.g.; of undiluted solution 602 a) can be takenduring the next step of integrated sensor system 600 operations. In someembodiments, the number of sequential flush movements is sufficient toonly wash substantially the sample from the sensor 14 and catheter lumen12 a. In other embodiments, the number of sequential flush movements canbe extended past the number of flush movements required to remove thesample from the sensor and catheter lumen, such as to provide additionalfluid to the host, for example.

At the completion of the flush step, the flow control device 604 returnsto step one, illustrated in FIG. 8A. In some embodiments, the stepsillustrated in FIGS. 8A through 8C are repeated, until the system 600 isdisconnected from the catheter/sensor, either temporarily (e.g., to movea host to an alternate location for a procedure) or permanently (e.g.,at patient discharge or expiration of sensor life time). In someembodiments, additional optional steps can be performed.

Optional Step: Keep Vein Open (KVO)

Thrombosis and catheter occlusion are known problems encountered duringuse of an IV system, such as when the fluid flow is stopped for a periodof time or flows at a too slow rate. For example, thrombi in, on and/oraround the catheter 12, such as at the catheter's orifice 12 b can causean occlusion. Occlusion of the catheter can require insertion of a newcatheter in another location. It is known that a slow flow of IVsolution (e.g., saline or calibration fluid; with or without heparin)can prevent catheter occlusion due to thrombosis. This procedure is knowas keep vein open (KVO).

In general, to infuse a fluid into a host, the infusion device mustovercome the host's venous and/or arterial pressure. For example, duringinfusion of a hydration fluid, the IV bag is raised to a height suchthat the head pressure (from the IV bag) overcomes the venous pressureand the fluid flows into the host. If the head pressure is too low, someblood can flow out of the body and in to the tubing and/or bag. Thissometimes occurs when the host stands up or raises his arm, whichincreases the venous pressure relative to the head pressure. Thisproblem can be encountered with any fluid infusion device and can beovercome with a KVO procedure. KVO can maintain sufficient pressure toovercome the host's venous pressure and prevent “back flow” of bloodinto the tubing and/or reservoir.

In some embodiments, the flow control device 604 can be configured toperform a KVO step, wherein the fluid flow rate is reduced (but notcompletely stopped) relative to the calibration and/or wash flow rates.In preferred embodiments, the KVO flow rate is sufficient to prevent thecatheter 12 from clotting off and is relatively lower than the flow rateused in step one (above). In preferred embodiments, the KVO flow rate issufficient to overcome the host vessel pressure (e.g., venous pressure,arterial pressure) and is relatively lower than the flow rate used instep one (above). In some embodiments, the KVO flow rate is from about1.0 μl/min or less to about 1.0 ml/min or more. In some preferredembodiments, the KVO flow rate is from about 0.02 to about 0.2 ml/min.In some more preferred embodiments, the KVO flow rate is from about 0.05ml/min to about 0.1 ml/min). In some embodiments, the KVO flow rate isless than about 60%, 50%, 40%, 30%, 20%, or 10% of the calibrationand/or flush flow rate(s). In some embodiments, the KVO step isperformed for from about 0.25 minutes or less to about 20 minutes ormore. In preferred embodiments, the solution 602 a flows at a rate suchthat the temperature of the solution 602 a substantially equilibrateswith the temperature of the tissue surrounding the in vivo portion ofthe catheter 12. Advantageously, equilibrating the solution 602 atemperature with that of the surrounding tissue reduces the effect oftemperature on sensor 14 calibration and/or sample measurement, therebyimproving sensor accuracy and consistency. In some embodiments, the KVOstep can be incorporated into one or more of the flow control devicesteps of operation described elsewhere herein, including steps one andtwo, and the flush step, above.

The KVO step can be executed in one or more ways. In some embodiments,the flow control device 604 can be configured to move to at least oneaddition position, wherein the tube 606 is partially pinched. Forexample, the flow control device 604 is configured to move to a positionsuch that the pinch point 808 is partially closed/open. For example, inthe embodiment shown in FIGS. 8A through 8C, the flow control device 604can be moved forward somewhat past position 812, such that the roller802 causes the tube 606 to be partially pinched. In another example, theflow control device 604 can be moved backwards somewhat behind position810, such that the roller 802 again causes the tube 606 to be partiallypinched. In preferred embodiment, the amount of pinch can be adjustedsuch that the desired KVO flow rate can be achieved. In some alternativeembodiments, KVO is performed by moving the flow control device betweenpositions 810 and 812 (e.g., see FIG. 8A) at a reduced speed, such thatthe flow rate is from about 0.1 μl/min or less to about 0.5 ml/min ormore. In some embodiments, the system is configured such that the timeof movement between the first and second discreet positions is fromabout 0.25 to 30 seconds, preferably from about 5 to 15 seconds. In somepreferred embodiments, the tubing is pinched fully closed (e.g., betweenstructures 802 and 806) during the movement from position 810 and 812(e.g., see FIG. 8A). In some preferred embodiments, after the flowcontrol device reaches position 812, the flow control device flips overthe top and back to position 810 (e.g., see FIG. 8C) at a substantiallyrapid speed that the flow rate remains substantially unchanged. In aneven further embodiment, during the KVO step the flow control devicealternates between the slow and fast movements at least two times, suchthat the KVO step lasts a period of time.

As disclosed above, the flow control device 604 can be configured avariety of ways, which can require modifications to one or more of thesteps of operation described above. For example, in some embodiments,the flow control device 604 can be configured to include a simple pinchvalve, wherein the valve can be configured to open, close or partiallyopen. In some embodiments, the flow control device 604 can be configuredto include a non-linear rolling pinch valve, wherein the roller can moveback and forth between opened, closed and partially opened positions,for example.

In some embodiments, the flow control device 604 can include one roller802 (e.g., first structure) attached to an axle 804 and configured topress against a curved surface 806 (e.g., second structure), such thatwhen the roller 802 is pressing against the curved surface 806 at orbetween positions 810 and 812, the tubing 606 is pinched completelyclosed and the flow control device 604 moves the roller 802 forward(e.g., toward the host). In one exemplary embodiment, the flow controldevice 604 can be configured to perform step one (above, contacting thesensor 14 with solution 602 a) by moving the roller 802 forward (e.g.,rotating from position 810 to 812, see FIG. 8A), thereby causingsolution 602 a to flow over the sensor 14. In some embodiments, the flowcontrol device 604 is configured to perform step two (contacting thesensor 14 with sample) by moving the roller 802 backwards (e.g.,rotating from position 812 to 810, see FIG. 8B), causing blood 814 toenter the catheter 12 and contact the sensor 14. Additionally, the flowcontrol device 604 can be configured to perform a wash or KVO step bymoving the roller 802 forward (from position 810) past position 812 andaround the axle 804 until position 810 is again reached a plurality oftimes sequentially (e.g., see FIG. 8C). In a further example, the flowcontrol device 604 includes two, three or more rollers 802 arrangedabout axle 804. In some embodiments, the flow control device includes aplurality of rollers arranged about the axle, wherein the flow controldevice performs KVO by rotating the rollers about the axle a pluralityof times, to continuously push (e.g., for a period of time) the solutionforward into the host.

In one alternative embodiment, back flow can be substantially stopped byincorporation of a one-way, pressure-controlled valve into the system,such as at or adjacent to the catheter or sensor connector, wherebyfluid can flow into the host only when fluid pressure (e.g., headpressure) is applied to the reservoir-side of the valve. In other words,fluid can only flow in the direction of the host (e.g., toward thehost), not backwards towards the reservoir. In some embodiments, thevalve is a two-way valve configured such that the pressure required toopen the valve is greater than the venous pressure, such that back flowis substantially prevented.

The preferred embodiments provide several advantages over prior artdevices. Advantageously, the movement of the solution 602 a and sampleoccur at a metered rate and are unaffected by changes in head pressure,such as but not limited to when the host elevates his arm or gets up tomove around. Also, sample loss to the host is minimized, first byreturning all collected samples to the host; and second by substantiallypreventing back-flow from the host (e.g., into the tubing or reservoir)with a “hard stop” (e.g., a point beyond which the flow control devicecannot move fluid into or out of the host). For example, in onepreferred embodiment, the flow control device can be configured todeliver no more than 25-ml of solution to the host per hour. In anotherexemplary embodiment, the flow control device can be configured to drawback no more than 100 μl of blood at any time. Advantageously, the flowrate of solution 602 a and sample 814 is carefully controlled, such thatboth the sample 814 and the solution 602 a remain substantiallyundiluted. Additionally, the solution 602 a warms to the host's localbody temperature, such that the integrated sensor system 600 issubstantially unaffected by temperature coefficient and sensor 14accuracy is increased.

Systems and Methods for Processing Sensor Data

In general, systems and methods for processing sensor data associatedwith the preferred embodiments and related sensor technologies includeat least three steps: initialization, calibration, and measurement.Although some exemplary glucose sensors are described in detail herein,the systems and methods for processing sensor data can be implementedwith a variety of analyte sensors utilizing a variety of measurementtechnologies including enzymatic, chemical, physical, electrochemical,spectrophotometric, polarimetric, calorimetric, radiometric, and thelike. Namely, analyte sensors using any known method, includinginvasive, minimally invasive, and non-invasive sensing techniques,configured to produce a data signal indicative of an analyteconcentration in a host during exposure of the sensor to a biologicalsample, can be substituted for the exemplary analyte sensor describedherein.

In some embodiments, the sensor system is initialized, whereininitialization includes application of the sensor and/or sensor systemin or on the host. In some embodiments, the sensor system includes acomputer system including programming configured for performing one ormore of the following functions: turning the system on, requestingand/or receiving initial data (e.g., time, location, codes, etc),requesting and/or receiving patient data (e.g., age, conditions,medications, insulin dosing, etc), requesting and/or receivingcalibration information (e.g., manufacturer calibration lot data,reference information such as solution(s) provided for calibration,etc.), and the like.

In some embodiments, the sensor system is configured with apredetermined initial break-in time. In some embodiments, the sensor'ssensitivity (e.g., sensor signal strength with respect to analyteconcentration) and/or baseline can be used to determine the stability ofthe sensor; for example, amplitude and/or variability of sensorsensitivity and/or baseline may be evaluated to determine the stabilityof the sensor signal. In alternative embodiments, detection of pHlevels, oxygen, hypochlorite, interfering species (e.g., ascorbate,urea, and acetaminophen), correlation between sensor and referencevalues (e.g., R-value), and the like may be used to determine thestability of the sensor. In some embodiments, the sensor is configuredto calibrate during sensor break-in, thereby enabling measurement of thebiological sample prior to completion of sensor break-in.

In one embodiment, systems and methods are configured to processcalibrated sensor data during sensor break-in. In general, signalsassociated with a calibration and/or measurement phase of the sensorsystem can be measured during initial sensor break-in. Using a ratemethod of measuring an analyte (e.g., measuring the rate of change of astep change), a sensor signal can be calibrated with a correction factorto account for the rate of change of the break-in curve. In oneexemplary embodiment, the bottom of sequential step responses (e.g., ofcalibration phases during sensor break-in) can be fit to a line or curve(e.g., using linear or non-linear regression, such as least squaresregression), to extrapolate the rate of change of the curve of thesensor break-in. Accordingly, the rate of change measured in ameasurement phase can be corrected to account for the rate of change ofthe sensor break-in curve, and the sensor signal calibrated. Bycalibrating during sensor break-in, sensor data can more quickly beprovided (e.g., to the user interface) after sensor insertion.

In some embodiments, systems and methods are configured to determine aninitial baseline value of the sensor. In general, baseline refers to acomponent of an analyte sensor signal that is not substantially relatedto the analyte concentration In one example of a glucose sensor, thebaseline is composed substantially of signal contribution due to factorsother than glucose (for example, interfering species,non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation potential that overlaps with hydrogen peroxide).

In preferred embodiments, the sensor system includes a computer systemincluding programming configured to determine calibration informationand calibrate a signal associated with a biological sample there from.In general, calibration of the signal includes initial calibration,update calibration and/or re-calibration of the sensor signal. Althoughsome systems and methods for calibrating a sensor are described in moredetail elsewhere herein, for example in the section entitled, “SensorElectronics,” additional and alternative methods for providingcalibration information and calibrating the sensor's signal are providedin the following description and can be used in combination with and/oralternative to the methods described elsewhere herein.

The term “calibration information” generally refers to any information,such as data from an internal or external source, which provides atleast a portion of the information necessary to calibrate a sensor. Insome embodiments, calibration information includes steady stateinformation, such as baseline information and/or sensitivity informationobtained by processing reference data from an internal and/or externalreference source, which is described in more detail elsewhere herein. Insome embodiments, calibration information includes transientinformation, such as rate of change information and/or impulse responseinformation obtained by processing a signal produced during exposure ofthe sensor to a step change (e.g., sudden or nearly sudden change) inanalyte concentration, which is described in more detail elsewhereherein.

In some embodiments, steady state information includes reference datafrom an external source, such as an analyte sensor other than the sensorof the sensor system configured to continuously measure the biologicalsample, also referred to as external reference data or externalreference value(s). In some embodiments, calibration informationincludes one, two, or more external reference values (e.g., fromself-monitoring blood glucose meters (finger stick meters), YSI GlucoseAnalyzer, Beckman Glucose Analyzer, other continuous glucose sensors,and the like). In some embodiments, one or more external referencevalues are requested and/or required upon initial calibration. In someembodiments, external reference value(s) are requested and/or requiredfor update calibration and/or re-calibration. In some embodiments,external reference values are utilized as calibration information forcalibrating the sensor; additional or alternatively, external referencevalues can be used to confirm the accuracy of the sensor system and/orto detect drifts or shifts in the baseline and/or sensitivity of thesensor.

In one exemplary embodiment, at least one external reference value incombination with at least one internal reference value together providecalibration information useful for calibrating the sensor; for example,sensitivity of a sensor can be determined from an external referencevalue and baseline can be at least partially determined from an internalreference value (e.g., a data signal indicative of an analyteconcentration in a reference solution during exposure of the sensor tothe reference solution, which is described in more detail elsewhereherein).

In another exemplary embodiment, calibration information includes two ormore external reference values that provide calibration informationuseful for calibrating the sensor; for example, at least two SMBG metervalues can be used to draw a calibration line using linear regression,which is described in more detail elsewhere herein.

In yet another exemplary embodiment an external reference value isutilized to confirm calibration information otherwise determined (e.g.,using internal reference values).

In some embodiments, steady state information includes reference dataobtained from the analyte sensor to be calibrated, also referred to asinternal reference data or internal reference values. In one exemplaryembodiment, internal reference data includes a signal associated withexposure of the sensor to one or more reference solutions (e.g.,calibration solutions), which is described in more detail elsewhereherein.

In some embodiments, the sensor system includes one or more referencesolutions (e.g., calibration solutions in some embodiments), wherein thesystem is configured to expose the sensor to the one or more referencesolution(s) to provide calibration information, such as baseline and/orsensitivity information for the sensor. In one exemplary embodiment, areference solution including a known analyte concentration is provided,wherein the system is configured to expose the sensor to the referencesolution, and wherein the system is configured to produce a data signalindicative of an analyte concentration in the reference solution duringexposure of the sensor to the reference solution, as described in moredetail elsewhere herein. In general the system can be configured toobtain internal reference values at one or more time points,intermittently, and/or continuously. Although much of the descriptionfocuses on the use of a reference calibration solution to provide aninternal reference value, other sensor technologies, such as opticalsensing methods, are known to provide one or more internal referencestandards (e.g., of known absorbance, reflectance, fluorescence, etc) todetermine baseline and/or sensitivity information, as is appreciated byone skilled in the art; accordingly, the systems and methods describedherein can be implemented with other types of internal reference values.

In some embodiments, the sensor system is configured to use a steadystate measurement method, from which steady state information can beobtained. Steady state information can be obtained during exposure ofthe sensor to an analyte concentration when the signal has reached a“plateau” wherein the signal is representative of the analyteconcentration; the term plateau does not limit the signal to a flatsignal, rather the plateau represents a time point or time period duringwhich the signal is substantially stable and a data point thatrepresents the analyte concentration can be reliably obtained.

FIG. 10 is a graph that schematically illustrates a signal producedduring exposure of the sensor to a step change in analyte concentration,in one exemplary embodiment. The x-axis represents time; the y-axisrepresents sensor signal (e.g., in counts). In general, a step changeoccurs when a sensor is sequentially exposed to first and seconddifferent analyte concentrations, wherein the signal (after the changefrom exposure of the sensor to the first analyte concentration toexposure of the sensor to the second analyte concentration) includes ameasurable rate of change (transient information) that subsequently“plateaus” or substantially “plateaus” to a signal that substantiallyrepresents the analyte concentration to which the sensor is exposed(steady state information). As one example, a step change occurs when asensor is exposed to a reference solution of a first analyteconcentration and then subsequently exposed to a reference solution of asecond, different, analyte concentration. As another example, a stepchange occurs when a sensor is exposed to a reference solution of aknown analyte concentration and then subsequently exposed to abiological sample of unknown or uncalibrated analyte concentration.

Referring to FIG. 10, at a first time point 1002, a sensor is exposed toa step change in analyte concentration, for example, from a zeroconcentration reference analyte solution to a biological sample ofunknown or uncalibrated analyte concentration. During the initial signalresponse to the step change, a rate of change 1004 of the signal can bemeasured for a time period. In some embodiments, for example when thestep change is between two known reference solutions, the rate of changeinformation can provide transient information useful for calibrating thesensor, which is described in more detail elsewhere herein. However, ifeither of the first and/or second analyte concentrations of the stepresponse is not known, the rate of change information, alone, cannotprovide sufficient calibration information necessary to calibrate thesensor.

Point 1006 represents a point in time that the signal response shiftsfrom transient information (e.g., rate of change) to steady stateinformation (e.g., plateau), in some embodiments. Namely, the signal,beginning at point 1006, substantially accurately represents the analyteconcentration and can be used in steady state equations to determine ananalyte concentration, in some embodiments. In one exemplary embodimentof steady state equations useful for calibrating the sensor system, thecalibration information is obtained by solving for the equation y=m×+b,wherein: “y” represents the sensor data value (e.g., digitized in“counts”) determined at a single point (or averaged value over a windowof data where signal is indicative of analyte concentration, forexample); “b” represents baseline (e.g., unrelated to the analyte); “m”represents sensitivity (e.g., for a glucose sensor, counts/mg/dL); and“x” is the concentration of the reference solution (e.g., known analyteconcentration in a reference calibration solution (e.g., glucose inmg/dL)). In this exemplary embodiment, steady state information includessensitivity and baseline.

In some embodiments, the sensor data value (y) can be obtained from amoving window that intelligently selects a plateau during exposure ofthe sensor to an analyte concentration. In some embodiments, the sensorsystem is configured to be exposed to two or more known referencecalibration solutions from which steady state information (sensitivityand baseline) can be processed to calibrate the sensor system; namely,by providing two known analyte concentrations, the steady state equationdescribed above can be utilized to solve for baseline and sensitivity ofthe sensor, which can be utilized to define a conversion function orcalibration factor, such as described in more detail elsewhere herein.

Referring again to FIG. 10, point 1006 is a point that can be used as“y” in the steady state equation described above. In some embodiments,the point 1006 is easily determinable as it is the beginning of a signalplateau 1008 (represented by a dashed line); accordingly, the systemincludes programming to process the data signal to determine the signalplateau and/or a time point therein. In general, a step change producesa signal plateau in the signal response, which is indicative of a steadystate response to the analyte concentration measurement. In someembodiments, the system includes programming configured determine thetime period (window) during which the signal has reached a plateau andchoose a single point or average point from that window.

In some situations, however, the point 1006 and/or plateau 1008 may notbe easily determinable. For example, in some sensor systems, thediffusion of certain non-analyte species (e.g., baseline, backgroundand/or interfering species), which may diffuse more slowly than theanalyte (e.g., through a membrane system that covers the analytesensor), do not reach a steady state during the same time period thatthe analyte reaches a steady state. In these situations, the signal maynot “plateau” in a measurable manner because of the reaction of thelagging species through the membrane system, which generate additionalsignal over the actual analyte plateau 1008. In other words, while theanalyte concentration may have reached a plateau, the baseline has not.Dashed line 1010 represents the signal response to a step change in sucha situation, for example, wherein the signal does not substantially“plateau” due to the lagging diffusion of certain non-analyte species,resulting in a non-measurable analyte plateau. In these situations,additional information is required in order to provide calibratedanalyte sensor data. Systems and methods for providing additionalinformation and/or to provide sufficient calibration information tocalibrate an analyte sensor in such situations are described in moredetail below, with reference to conjunctive measurements, for example.

In some embodiments, the sensor system is exposed to a referencesolution with a known analyte concentration of about zero, and whereinthe steady state information comprises baseline information about thesensor in the reference solution. For example, a glucose sensor systemcan be exposed to a 0 mg/dl glucose solution (e.g., saline solutionwithout any glucose concentration) and the signal associated with thezero glucose concentration in the reference solution providescalibration information (steady state) indicative of at least a portionof the baseline of the sensor. However, the signal associated with thezero glucose concentration in a reference solution (such as saline) maynot be equivalent to the baseline signal when the sensor is exposed to abiological sample (e.g., blood) from which the sensor is configured toobtain its analyte concentration measurement; accordingly, additionalcalibration information may be required in order to determine baselineof a biological sample (e.g., blood) in some embodiments. In someembodiments, the calibration solution includes additional componentsprovided to overcome baseline in blood, for example. In someembodiments, a factor can be determined (e.g., from historical data) todetermine an adjustment factor for a difference between baseline in thebiological sample (e.g., blood) and baseline in the reference solution.In some embodiments, the difference in baseline of a biological sample(e.g., blood) and the baseline of the reference solution, also referredto as b_(offset) herein, can be determined using other techniques, suchas described in more detail below.

In general, the calibration information described above, including aknown baseline and sensitivity, can be used to determine a conversionfunction or calibration factor applied to convert sensor data (“y”) intoblood glucose data (“x”), as described in more detail elsewhere herein.

In some embodiments, systems and methods are configured to obtaintransient measurement information associated with exposure of the sensorto a reference solution of known analyte concentration and/or abiological fluid of unknown or uncalibrated analyte concentration. Insome embodiments, the system is configured obtain transient informationby exposing the sensor to a step change in analyte concentration andprocess the rate of change of the associated signal. In someembodiments, the system is configured to obtain transient information byexposing the sensor to a step change in analyte concentration andprocessing the impulse response of the associated signal.

In one exemplary embodiment, the sensor is exposed to a first referencesolution of a known analyte concentration and then to a second referencesolution of a known analyte concentration to determine the rate ofchange of the signal response. In these embodiments, the equation(Δy/Δt=r·Δx) can be used to obtain the transient information, wherein“Δx” is the difference between the two known solutions that are beingmeasured (e.g., 0 mg/dL to 100 mg/dL in an exemplary glucose sensor),“Δy” is the measured difference between the sensor data (e.g., incounts) corresponding to the analyte concentration difference in knownreference solutions (Δx), “Δt” is the time between the two “y” sensormeasurements referenced with Δy, and “r” represents the rate of changecalibration factor, or rate of change conversion function, that can beapplied for that particular sensor to obtain calibrated blood glucosemeasurements from sensor rate of change data.

In some embodiments, transient information can be obtained from the rateof change of a signal produced during exposure of the sensor to abiological sample of unknown or uncalibrated analyte concentration. Insome embodiments, transient information can be obtained from the stepand/or impulse response of a signal produced during exposure of thesensor to a step change in analyte concentration.

In some embodiments, neither steady state information, nor transientcalibration measurements are used in isolation in calibrating the sensorsystem, but rather steady state and transient information are combinedto provide calibration information sufficient to calibrate sensor datasuch as described in more detail, below. For example, in someembodiments, wherein baseline is not completely known (e.g., b_(offset)must be determined), wherein a rate of change calibration factor is noteasily determinable (e.g., when multiple known reference solutionscannot be pushed substantially immediately adjacent to each other toprovide a rate of change indicative of the step or impulse response),wherein the a steady state measurement cannot be obtained (e.g., due tolagging species affecting the analyte signal plateau), and the like. Insome embodiments, both steady state information and transientinformation are processed by the system to provide sensor calibration,confirmation, and/or diagnostics. In some embodiments, transient sensorinformation from unknown or uncalibrated blood glucose measurements canbe processed to provide calibration information for the sensor system,such as described in more detail below.

In some embodiments, once at least a portion of the calibrationinformation is determined, the sensor system is configured to expose thesensor to a biological sample and measure a signal response thereto. Insome embodiments, the sensor can be continuously exposed to thebiological sample, wherein at least some external reference values areused as calibration information for calibrating the sensor system. Insome embodiments, the sensor can be intermittently exposed to thebiological sample, wherein at least some internal reference values areused as calibration information for calibrating the sensor system, alsoreferred to as auto-calibration in some exemplary embodiments.

In some embodiments, the sensor system is calibrated solely using steadystate information, such as described in more detail elsewhere herein. Inone such embodiment, the sensor system is configured to be exposed to abiological sample and a value (y) determined from the signal plateau,which is used in combination with a conversion function (calibrationfactor) that uses steady state information (e.g., sensitivity andbaseline) to obtain a calibrated analyte concentration (e.g., glucoseconcentration in mg/dL or mmol/L) equivalent to the measured sensor datavalue y.

In general, the sensor system of the preferred embodiments can beconfigured to utilize any combination the steady state information(e.g., from external and/or internal sources) described in more detailelsewhere herein. In some embodiments, the sensor system includessystems and methods configured to calibrate the sensor based on one,two, or more external reference values. In some embodiments, the sensorsystem includes systems and methods configured to calibrate the sensorbased on one or more external reference values, which calibration can beconfirmed using an internal reference value (e.g., zero analyteconcentration reference solution). In some embodiments, the sensorsystem includes systems and methods configured to calibrate the sensorbased on one external reference value in combination with one internalreference value to determine baseline and sensitivity information. Insome embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based on internal reference values,also referred to as auto-calibration. In general, auto-calibrationincludes the use of one or more reference solution to calibrate thesensor system. In some embodiments, the sensor system includes systemsand methods configured to calibrate the sensor based on priorinformation, which is described in more detail elsewhere herein. In someembodiments, the sensor system includes systems and methods configuredto calibrate the sensor based on dual working electrodes, bysubstantially eliminating the baseline component of the steady statecalibration equation (e.g., (y=mx)).

In some embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based solely on transient information(e.g., rate of change, decay, impulse response, etc) described in moredetail elsewhere herein. In one exemplary embodiment, analyteconcentration can be determined from the change in sensor dataresponsive to a step change (Δx), the time (Δt) elapsed between thesensor data measurements Δy, and the rate of change calibrationfactor/rate of change conversion function, such as described in moredetail above.

In some embodiments, the sensor system includes systems and methodsconfigured to calibrate the sensor based on conjunctive information,wherein the calibration information used to calibrate the sensor systemincludes both steady state information and transient information.

In one exemplary embodiment, the sensor system includes systems andmethods configured to calibrate the sensor based on a rate of change(transient information) associated with a signal produced duringexposure of the sensor to a step change between a reference solution ofknown analyte concentration (e.g., 0 mg/dl glucose) and a biologicalsample; in this exemplary embodiment, a reference value (steady stateinformation) from an external analyte sensor (e.g., blood glucose meter)can be obtained for the analyte concentration in the biological sample,thereby providing sufficient information to solve for calibration usingrate of change of the signal response to the step change there between.One advantage of using rate of change calibration methods includes itsinsensitivity to baseline and interfering species.

In one preferred embodiment, a system is provided for monitoring analyteconcentration in a biological sample of a host, the system including: asubstantially continuous analyte sensor configured to produce a datasignal indicative of an analyte concentration in a host during exposureof the sensor to a biological sample; a reference solution including aknown analyte concentration, wherein the system is configured to exposethe sensor to the reference solution, and wherein the sensor isconfigured to produce a data signal indicative of an analyteconcentration in the reference solution during exposure of the sensor tothe reference solution; and a computer system including programmingconfigured to determine calibration information and calibrate a signalassociated with a biological sample there from, wherein the calibrationinformation includes steady state information and transient information.In some embodiments, the calibration information is determined from asignal associated with exposure of the sensor to the reference solutionand a signal associated with exposure of the sensor to a biologicalsample.

One situation wherein steady state information and transient informationare useful together for calibrating a sensor system includes a situationwhere a baseline measurement obtained from an internal reference(b_(reference)) provides only a portion of the baseline informationnecessary for calibrating the sensor system. As one example, thebaseline of blood is different from the baseline of saline (e.g.,reference) and compounds or molecules that make up the baseline in bloodcan create artifacts (e.g., b_(offset)), which can make calibrationusing internally derived steady state information alone, difficult.Namely, plateau 1008 (FIG. 10) in the signal responsive to the stepchange in analyte concentration does not occur in blood, in someembodiments, due to slow diffusion of baseline-causingcompounds/molecules to the sensor electroactive surface; instead, anartifact 1010 (FIG. 10) is observed in the signal. Accordingly, in someembodiments, baseline information useful for calibration of a sensorsystem includes both b_(reference) and b_(offset). A variety of systemsand methods of determining b_(offset), which can be useful in providingcalibration information and/or diagnostics and fail-safes, has beendiscovered, as described in more detail elsewhere herein.

In some embodiments, b_(offset) can be determined from transientinformation derived from a signal associated with exposure of the sensorto a biological sample, wherein the biological sample is of unknown oruncalibrated analyte concentration.

In one preferred embodiment, a system for monitoring analyteconcentration in a biological sample of a host is provided, the systemincluding: a substantially continuous analyte sensor configured toproduce a data signal indicative of an analyte concentration in a hostduring exposure of the sensor to a biological sample; a referencesolution including a known analyte concentration, wherein the system isconfigured to expose the sensor to the reference solution, and whereinthe system is configured to produce a data signal indicative of ananalyte concentration in the reference solution during exposure of thesensor to the reference solution; and a computer system includingprogramming configured to determine calibration information andcalibrate a signal associated with a biological sample there from,wherein the calibration information is determined from a signalassociated with exposure of the sensor to the reference solution and asignal associated with exposure of the sensor to a biological sample,wherein the biological sample is of unknown or uncalibrated analyteconcentration.

In some embodiments, systems and methods are configured to process animpulse response of a signal associated with exposure of the sensor to abiological sample, wherein the biological sample is of unknown oruncalibrated analyte concentration, in order to determine an offsetbetween a baseline measurement associated with a reference solution anda baseline measurement associated with a biological sample (e.g.,b_(offset)).

FIG. 11 is a graph that schematically illustrates a derivative of thestep response shown in FIG. 10. FIG. 11 can also be described, as theimpulse response of the signal associated when a sensor is exposed to astep change to a biological sample of unknown or uncalibrated analyteconcentration, in one exemplary embodiment. In this embodiment, theimpulse response can be defined by a sum of two exponentials functions(e.g., (ae^(−k1*t)-ae^(−k2*t)), where k1 and k2 are time constantscharacteristic of the sensor), wherein the impulse response starts at 0at t=0 and is expected to decay to 0 as t becomes large (as timepasses). The impulse response reaches a peak, shown as point 1050 inFIG. 11, which represents the maximum rate of change of the associatedsignal (see FIG. 10, for example). Additionally, although it is expectedthat the signal will decay to 0 as t becomes large, FIG. 11 illustratesa plateau 1052 above the y-axis; namely, wherein the plateau 1052 doesnot hit 0.

It has been discovered that the positive value 1054 of the plateausubstantially represents the slope of the b_(offset) artifact 1010 (FIG.10). Accordingly, when the slope is drawn from t=0 of the step response(see line 1012 of FIG. 10), the “y” value 1016 of that slope line at theend of the step response 1014, represents b_(offset). Accordingly,b_(offset) can then be added to the equation y=m×+b (whereb=b_(reference)+b_(offset)) and a conversion function (calibrationfactor) can be determined to calibrate the sensor system (i.e., usingboth steady state information and transient information and includingusing the signal associated with exposure of the sensor to a biologicalsample of unknown or uncalibrated analyte concentration.)

In some alternative embodiments, systems and methods are configured toprocess an impulse response (such as shown in FIG. 11) associated with astep change (such as shown in FIG. 10) to determine a time point of asteady state measurement during which an analyte concentration can beobtained. As described above, in some circumstances, it can be difficultto determine a steady state time point (e.g., 1006 in FIG. 10) at whichtime point the signal accurately represents the analyte concentration.Accordingly, systems and methods configured to determine the time point(e.g., 1006 in FIG. 10) in the step response associated with exposure ofthe sensor to a biological sample of unknown or uncalibrated analyteconcentration have been discovered, which time point accuratelyrepresents the analyte concentration in the biological sample. Becausethe impulse response can by defined by exponentials (discussed above),systems and methods can be configured to process the exponentialequation (s) with variable parameters to determine a best-fit to theimpulse response curve determined from exposure of the sensor to thebiological sample. It has been discovered that this best fit of theimpulse response provides sufficient information to determine the timepoint 1056 (FIG. 11) at which the decay curve should have decayed to they-intercept; namely, the time point 1056 where the decay curve shouldhave hit y=0 indicates the (steady state) time point in the stepresponse (e.g., 1006 in FIG. 10) that accurately represents the analyteconcentration without the b_(offset) artifact 1010. Accordingly,(y=m×+b) can then be used to calibrate the sensor system, including thesignal value “y” at the time indicated by the extrapolated impulseresponse curve (e.g., and using sensitivity and baseline informationdetermined from one or more reference calibration solutions, such asdescribed in more detail elsewhere herein.

In some other alternative embodiments, systems and methods areconfigured to compare steady state information and transient informationfor a plurality of time-spaced signals associated with biologicalsamples of unknown or uncalibrated analyte concentration to determine anoffset between a baseline measurement associated with a referencesolution and a baseline measurement associated with the biologicalsamples.

In some exemplary embodiments, b_(offset) is determined by plottinglevel (i.e., the point at which the step response plateaus or ends) vs.rate (i.e., maximum rate of change of the step response determined fromthe peak of the impulse response curve) for a plurality of stepresponses (e.g., time-spaced signals) and drawing a regression line ofthe plotted points, such as described in more detail with reference toFIG. 12.

FIG. 12 is a graph that illustrates level vs. rate for a plurality oftime-spaced signals associated with exposure of the sensor to biologicalsamples of unknown or uncalibrated analyte concentration. The y-axisrepresents maximum rate of change for each step response; the x-axisrepresents level (signal level (e.g., in counts) obtained at the plateauof the signal and/or the end of the step response.) Each point 1080 onthe plot represents level vs. rate for each of the plurality oftime-spaced signals. A regression line 1082 is drawn using knownregression methods, as is appreciated by one skilled in the art. Thepoint 1084 at which the line 1082 crosses the y-axis represents thesignal associated with a reference (e.g., 100 mg/dL calibrationsolution) plus b_(offset). Accordingly, b_(offset) can be determined bysubtracting the signal associated with the reference from the point 1084at which the line 1082 crosses the y-axis. Thus, b_(offset) determinedfrom the plot as described above, can be included in the equation y=m×+b(where b=b_(reference)+b_(offset)) and a conversion function(calibration factor) can be determined to calibrate the sensor system(i.e., using both steady state information and transient information andincluding using the signal associated with exposure of the sensor to abiological sample of unknown or uncalibrated analyte concentration.)

In some embodiments, b_(offset) is an adjustable parameter, wherein thesensor system includes systems and methods configured to determineb_(offset) with each measurement cycle (each time the sensor is exposedto the biological sample) and to adjust the calibration factor(conversion function), including b_(offset) with each measurement cycle,responsive to a change in b_(offset) above a predetermined threshold,and/or responsive to external information, for example.

In some embodiments, systems and methods are provided to detect a shiftin the baseline and/or sensitivity of the signal based on a comparisonof steady state information and transient information, such as describedin more detail with reference to FIG. 12. In some embodiments, systemsand methods are provided to correct for a shift in the baseline and/orsensitivity of the signal based on a comparison of steady stateinformation and transient information. In some embodiments, systems andmethods are provided to initiate a calibration responsive to detectionof a shift in the baseline and/or sensitivity of the signal based on acomparison of steady state information and transient information.

Referring again to FIG. 12, regression line 1082 is shown for a selectedplurality of time spaced signals. In some embodiments, multipleregression lines can be drawn for a plurality of different windows oftime spaced signals (e.g., time-shifted windows). In these embodiments,a comparison of a regression line from a first window of time spacedsignals as compared to a regression line drawn from a second window oftime spaced signals can be used to diagnose a shift and/or drift insensor sensitivity and/or baseline. For example, in FIG. 12, line 1082represents a regression line drawn for a first window of data over afirst period of time; dashed line 1086 represents a regression linedrawn for a second window of data over a second period of time; anddashed line 1088 represents a regression line drawn for a third windowof data over a third period of time. In this example, dashed line 1086is shifted along the y-axis from the first line 1082, indicating a driftor shift in the sensor's baseline from the first time period to thesecond time period; dashed line 1088 is shifted along the x-axis fromthe first line 1082, indicating a drift or shift in the sensor'ssensitivity from the first time period to the third time period.Accordingly, a shift in the regression line can be used to diagnose ashift or drift in the sensor's signal and can be used to trigger acorrective action, such as update calibration and/or re-calibrationusing any of the methods described herein. Additionally oralternatively, the shift in the line can be used to correct a shift ordrift in the sensor's signal; for example, the amount of shift in theline can be used to update calibration accordingly (e.g., the change iny-value between two regression lines can be representative of acorresponding change in baseline between two time periods, and thecalibration information updated accordingly). One skilled in the artappreciates that some combination of shift or drift of the baseline andsensitivity can occur in some situations, which can be similarlydetected and/or corrected for.

Diagnostics and Fail-Safes

In some embodiments, the system includes programming configured todiagnose a condition of at least one of the sensor and the hostresponsive to calibration information. In some embodiments, the systemintermittently or continuously determines at least some calibrationinformation (e.g., sensitivity information, b_(offset), and the like),each time the sensor is exposed to a reference solution and/or abiological sample.

In one embodiment, systems and methods are configured to find a plateauand/or stable window of data in response to exposure of the sensor to atleast one of a reference solution and a biological sample. In someembodiments, if the system cannot find the plateau and/or stable windowof data, the system is configured to “fail-safe;” for example, in somecircumstances, a lack of plateau and/or stable window of data may beindicative of dilution and/or mixture of the reference solution (e.g.,calibration solution) with the biological sample (e.g., blood), and/orinterruption/disruption of expected/desired fluid flow. Additionally, insome circumstances, a lack of plateau and/or stable window of data maybe indicative of interfering species in the signal.

In general, the term “fail-safe” includes modifying the systemprocessing and/or display of data in some manner responsive to adetected error, or unexpected condition, and thereby avoids reportingand/or processing of potentially inaccurate or clinically irrelevantanalyte values.

In another embodiment, systems and methods are configured to process asignal responsive to exposure of the signal to a reference and/orbiological sample to determine whether the signal is within apredetermined range; if the signal falls outside the range, the systemis configured to fail-safe.

In some embodiments, systems and methods are configured to determinecalibration information including sensitivity information, wherein thesystem includes programming configured to diagnose an error responsiveto a change in sensitivity above a predetermined amount. For example, ina sensor system as described in more detail with reference to theexemplary embodiment of FIGS. 8A to 8C, the system can be configured todetermine a sensitivity value during each calibration phase; and whereinthe system can be configured to fail-safe when the sensitivity of acalibration phase differs from the previously stored sensitivity by morethan a predetermined threshold. In this exemplary embodiment, fail-safecan include not using the sensitivity information to update calibration,for example. While not wishing to be bound by theory, the predeterminedthreshold described above allows for drift in the sensitivity of thesensor, but prevents large fluctuations in the sensitivity values, whichmay be caused by noise and/or other errors in the system.

In some embodiments, systems and methods are configured to diagnoseerror in the sensor system by ensuring the sensor signal (e.g., rawsignal of the reference solution(s)) is within a predetermined range. Insome embodiments, the sensor signal must be within a predetermined rangeof raw values (e.g., counts, current, etc). In some embodiments, one ormore boundary lines can be set for a regression line drawn from thecalibration phase. For example, subsequent to performing regression, theresulting slope and/or baseline are tested to determine whether theyfall within a predetermined acceptable threshold (boundaries). Thesepredetermined acceptable boundaries can be obtained from in vivo or invitro tests (e.g., by a retrospective analysis of sensor sensitivitiesand/or baselines collected from a set of sensors/patients, assuming thatthe set is representative of future data). Co-pending U.S. patentapplication Ser. No. 11/360,250, filed on Feb. 22, 2006 and entitled,“ANALYTE SENSOR,” which is incorporated herein by reference in itsentirety, describes systems and methods for drawing boundaries lines. Insome embodiments, different boundaries can be set for differentreference solutions.

In some embodiments, systems and methods are configured for performingdiagnostics of the sensor system (e.g., continuously or intermittently)during exposure of the sensor to a biological sample, also referred toas the measurement phase, for example, such as described in more detailabove with reference to FIGS. 8A to 8C. In some embodiments, diagnosticsincludes determination and/or analysis of b_(offset). In someembodiments, systems and methods are provided for comparing sequentialb_(offset) values for sequential measurement phases. In someembodiments, the system includes programming configured to diagnose anerror and fail-safe responsive to a change in the b_(offset) above apredetermined amount. In some embodiments, the system includesprogramming configured to re-calibrate the sensor responsive to changesin the b_(offset) above a predetermined amount. In some embodiments, thesystem includes programming configured to detect an interfering speciesresponsive to a change in the b_(offset) above a predetermined amount.

In some embodiments, the system includes programming configured todiagnose a condition of the host's metabolic processes responsive to achange in b_(offset) above a predetermined amount. In some embodiments,the system includes programming configured to display or transmit amessage associated with the host's condition responsive to diagnosingthe condition. While not wishing to be bound by theory, it is believedthat changes in b_(offset) can be the result of an increase (ordecrease) in metabolic by-products (electroactive species), which may bea result of wounding, inflammation, or even more serious complicationsin the host; accordingly, changes in b_(offset) can be useful indiagnosing changes in the host's health condition.

In some embodiments, the system includes programming configured todetect sensor error, noise on the sensor signal, failure of the sensor,changes in baseline, and the like, responsive to a change in b_(offset)above a predetermined amount.

In some embodiments, the system includes programming configured todetermine a time constant of the sensor. One method of calculating atime constant for a sensor includes determining an impulse response to astep change, wherein time at the peak of the impulse response representsa time constant for the sensor. While not wishing to be bound by theory,it is believed that the time constant determined from the peak of theimpulse response should remain substantially the same throughout thelife of the sensor. However, if a shift in the time constant (betweenstep changes and their associated impulse response curves) above apredetermined range is detected, it can be indicative of an unexpectedsensor condition or error, for example. Accordingly, by comparing timeconstants from a plurality of impulse response curves (derived from aplurality of step responses), programming can be configured to diagnosea sensor condition or error and initiate programming (e.g., fail-safe),accordingly.

Accordingly, the system can “fail-safe,” including performing one ormore of the following fail-safe responses: temporarily or permanentlysuspending (e.g., discontinuing) display of analyte data, updatingcalibration or re-calibrating the sensor, requesting external referencevalues, using external reference value(s) as confirmation of a detectedcondition, using external reference value(s) to update calibration orre-calibrate the sensor, shutting the system down, processing the sensordata to compensate for the change in b_(offset), transmitting one ormore messages to the user interface or other external source regardingthe sensor condition, and the like.

Auto-Calibration

Some preferred embodiments are configured for auto-calibration of thesensor system, wherein “auto-calibration” includes the use of one ormore internal references to calibrate the sensor system. In someembodiments, auto-calibration includes systems and methods configured tocalibrate the sensor based solely on internal reference values. However,in some alternative embodiments of auto-calibration, one or moreexternal reference values can be used to complement and/or confirmcalibration of the sensor system.

In some preferred embodiments, the system is configured tointermittently expose the sensor to a biological sample; howeverconfigurations of the sensor system that allow continuous exposure ofthe sensor to the biological sample are contemplated. In someembodiments, the system is configured to intermittently or periodicallyexpose the sensor to a reference, however configurations of the sensorsystem that allow one or more independent or non-regular referencemeasurements initiated by the sensor system and/or a user arecontemplated. In the exemplary embodiment of a sensor system such asdescribed with reference to FIGS. 8A to 8C, the system is configured tocycle between a measurement phase and calibration phase (with optionalother phases interlaced therein (e.g., flush and KVO)).

In general, timing of auto-calibration can be driven by a variety ofparameters: preset intervals (e.g., clock driven) and/or triggered byevents (such as detection of a biological sample at a sensor). In someembodiments, one or more of the phases are purely clock driven, forexample by a system configured to control the timing housed within aflow control device, remote analyzer, and/or other computer system. Insome embodiments, one or more of the phases are driven by one or moreevents, including: exposure of the sensor to a biological sample (e.g.,blood) exposure of sensor to a reference (e.g., calibration solution),completion of calibration measurement, completion of analytemeasurement, stability of signal measurement, sensor for detecting abiological sample, and the like.

In one exemplary embodiment, calibration and measurement phases aredriven by cleaning of sensor; namely, systems and methods are configuredto detect when the sensor is in the biological sample and/or in thereference solution (e.g., calibration solution), wherein the system isconfigured to switch to appropriate phase responsive to detection ofthat sample/solution.

In another exemplary embodiment, an AC signal is placed on top of a DCsignal (e.g., in an amperometric electrochemical analyte sensor),wherein systems and methods are configured to analyze an impedanceresponse to the AC signal and detect a biological sample thereby.

In yet another exemplary embodiment, systems and methods are configuredfor analyzing the sensor's signal, wherein a change from a knownreference solution (e.g., a known analyte concentration) can be detectedon the signal, and the switch from the calibration phase to themeasurement phase occur responsive thereto; similarly, the system can beconfigured to switch back to the calibration phase responsive todetection of the known signal value associated with the referencesolution.

In yet another exemplary embodiment, systems and methods are configuredto switch between phases responsive to one or more sensors configured todetect the biological sample and/or reference solution at a particularlocation.

In some embodiments, the sensor system is partially or fully controlledby a clock (e.g., predetermined time intervals), which timing can beconfirmed by any of the events (e.g., triggers or sensors) describedabove.

In one exemplary embodiment, systems and methods are provided to enableauto-calibration of an integrated glucose sensor system with minimaluser interaction. In this exemplary embodiment, the integrated sensorsystem is provided with the components described above, including afluids bag, a flow control device, IV tubing, a flow control device, aremote analyzer, a local analyzer and a sensor/catheter, for example. Atsystem start-up, a health care worker inserts the catheter and sensorinto a host and injects a first reference solution (e.g., zero glucosesaline solution) into the IV tubing, wherein the system is configured toallow a predetermined time period (e.g., 20 minutes) for the firstreference solution to pass through the IV tubing and into the catheter.Subsequently, the health care worker couples the fluids bag to the IVtubing, wherein the fluids bag includes a second reference solution(e.g., 100 mg/dl glucose solution) configured to follow the firstreference solution in the IV line. After injecting the first referencesolution and coupling the second reference solution, the health careworker initiates the integrated sensor system (e.g., through the remoteanalyzer touch screen) after which the integrated sensor systemautomatically calibrates and functions for 24 hours without necessaryuser interface (for system calibration and/or initiation). In someembodiments, the sensor system is re-calibrated every 24 hours byinjection of a new first reference solution (e.g., zero glucose salinesolution).

In the above-described exemplary embodiment, the system is configured tocalibrate the sensor with the first and second reference solution andusing the methods described in the section entitled, “Systems andMethods for Processing Sensor Data.” Additionally, the system isconfigured to automatically detect the difference in signal associatedwith the first and second reference solutions, for example, throughsteady state detection of a difference in signal level.

EXAMPLES Example 1 Glucose Sensor System Trial in Dogs

Referring now to FIG. 4, glucose sensor systems of the embodiment shownin FIG. 1 were tested in dogs. The glucose sensors were built accordingto the preferred embodiments described herein. Namely, a first sensor(Test 1) was built by providing a platinum wire, vapor-depositing theplatinum with Parylene to form an insulating coating, helically windinga silver wire around the insulated platinum wire (to form a “twistedpair”), masking sections of the electroactive surface of the silverwire, vapor-depositing Parylene on the twisted pair, chloridizing thesilver electrode to form a silver chloride reference electrode, andremoving a radial window on the insulated platinum wire to expose acircumferential electroactive working electrode surface area thereon,this assembly also referred to as a “parylene-coated twisted pairassembly.”

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution and drying. An enzyme domain was formed over theelectrode domain by subsequently dip coating the assembly in an enzymesolution and drying. A resistance domain was formed over the enzymedomain by spraying the resistance domain solution on the sensorconstruct.

After the sensor was constructed, it was placed in the protective sheathand then threaded through and attached to the fluid coupler.

A second sensor (Test 2) was constructed in the same manner as thefirst, except that the silver wire was disposed within (e.g., coiledwithin) the fluid coupler. Accordingly, only the platinum workingelectrode (a single wire) was inserted into the catheter during theexperiment.

Prior to use, the sensors were sterilized using electron beam.

The forelimb of an anesthetized dog (2 years old, 40 pounds) was cutdown to the femoral artery and vein. An arterio-venous shunt was placedfrom the femoral artery to the femoral vein using 14 gauge catheters and⅛-inch IV tubing. A pressurized arterial fluid line was connected to thesensor systems at all times. The test sensor systems (test 1 and test 2)included a 20 gauge×1.25-inch catheter and took measurements every 30seconds. The catheter was aseptically inserted into the shunt, followedby insertion of the sensor into the catheter. A transcutaneous glucosesensor (control) of the type disclosed in U.S. Publ. No.US-2006-0155180-A1 was built and placed in the dog's abdomen accordingto recommended procedures. The dog was challenged with continuousincremental IV infusion of a 10% dextrose solution (“glucose challenge”)until the blood glucose concentration reached about 400 mg/dL.

FIG. 4 shows the experimental results. The thick line represents datacollected from the Test 1 sensor. The thin line represents datacollected from the Test 2 sensor. Diamonds represent data collected froma hand-held blood glucose meter (SMBG) sampled from the dog's abdomen.Raw glucose test data (counts) are shown on the left-hand Y-axle,glucose concentrations for the “SMBG” controls are shown on theright-hand y-axle, and time is shown on the X-axle. Each time intervalon the X-axle represents 29-minutes (e.g., 10:04 to 10:33 equals 29minutes). Immediately upon insertion into a catheter, each test sensorbegan collecting data with substantially no sensor equilibration time(e.g., break-in time). Each test sensor responded to the glucosechallenge substantially similarly to the control sensor. For example,each device shows the glucose signal increasing from about 3200 countsat 10:33 to about 6000-6700 counts at 11:31. Then, each device showed arapid decrease in glucose signal, to about 4700 counts at 12:00.Additionally, the response of the test sensors and the control sensorwere substantially similar (e.g., the majority of the test data wassubstantially equivalent to the SMBG data at each time point). Fromthese experimental show that an indwelling glucose sensor system (asdescribed herein) in contact with the circulatory system can providesubstantially continuous glucose monitoring in a clinical setting.

Example 2 Glucose Sensor System Trial in Pigs

Referring now to FIG. 5, four glucose sensor systems of the embodimentshown in FIG. 1 were tested in a pig (˜104 lb), using the protocoldescribed for Example 1, above. Glucose was continuously infused atincreasing rates through a distally placed IV catheter until a readoutof 300-400 mg/dl blood glucose was achieved (total 300 ml of a 10%dextrose IV solution). FIG. 5 shows the experimental results. Linesindicated the data from the four sensors (Test 1 through Test 4).Diamonds represent control measurements made with a hand-held glucosemeter (SMBG). Raw glucose test data (counts) are shown on the left-handY-axle, glucose concentrations for the “SMBG” controls are shown on theright-hand y-axle, and time is shown on the X-axle. Test results showthat though the sensors varied in sensitivity, each test sensorresponded to glucose challenge substantially similarly to the controlsensor (SMBG). These experimental results show that an indwellingglucose sensor system (of the preferred embodiments) in contact with thecirculatory system can substantially continuously track glucose in aclinical setting.

Example 3 Glucose Sensor System with Flow Control Device Trial in Pigs

Referring now to FIG. 13, a glucose sensor was built according to thepreferred embodiments described herein. Namely, a test sensor was builtby providing a platinum wire, vapor-depositing the platinum withParylene to form an insulating coating, helically winding a silver wirearound the insulated platinum wire (to form a “twisted pair”), maskingsections of the electroactive surface of the silver wire,vapor-depositing Parylene on the twisted pair, chloridizing the silverelectrode to form a silver chloride reference electrode, and removing aradial window on the insulated platinum wire to expose a circumferentialelectroactive working electrode surface area thereon, this assembly alsoreferred to as a “parylene-coated twisted pair assembly.”

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution and drying. An interference domain was formed overthe electrode domain by subsequently dip coating the assembly in aninterference domain solution and drying. An enzyme domain was formedover the interference domain by subsequently dip coating the assembly inan enzyme solution and drying. A resistance domain was formed over theenzyme domain by spraying the resistance domain solution on the sensorconstruct.

The test sensor was then located within a 20 gauge catheter and insertedin the femoral vein of a non-diabetic pig. The catheter was connected toan integrated sensor system 600 of the preferred embodiments. The flowcontrol device 604 (e.g., a roller valve as depicted in FIGS. 8A-8C) wasconfigured to move between steps one and two, as described in thesection entitled “Flow Control Device Function,” above. A 107-mg/dLglucose solution was used to calibrate the sensors (e.g., flows from thereservoir 602, through the tubing 606, to the catheter 12). To mimic adiabetic's hyperglycemic state, a gradual infusion of 26% dextrose wasgiven, until the pig's blood glucose was about 600 mg/dl. Then to mimica hypoglycemic state, 10 U Humulin N was given, until the pig's bloodglucose was about 50 mg/dl. Then, the pig's blood glucose was raised toabout 100 mg/dl by a second 26% dextrose infusion.

FIG. 13 is a graphical representation showing uncalibrated glucosesensor data and corresponding blood glucose values over time in a pig.Raw counts are represented on the left Y-axis. Glucose concentration isshown on the right Y-axis. Time is shown on the X-axis. Testmeasurements (e.g., measurements of blood glucose concentration obtainedwith the test sensor, raw counts) are shown as small, black dots.Control measurements (e.g., jugular vein blood samples analyzed on aYellow Springs Instrument (YSI) glucose analyzer) are shown as diamonds.

During the experiment, the system was configured to alternate betweencalibration measurements (with the 107 mg/dl glucose solution) and bloodglucose measurements, as described in the sections entitled “Step one:Contacting Sensor with Calibration Solution and Calibration” and “StepTwo: Sample Collection and Measurement,” respectively. Accordingly, asthe experiment proceeded the test signal oscillated between calibrationsolution (107 mg/dl) and blood glucose measurements. The sensor (test)blood glucose measurement correlated tightly with the control bloodglucose measurements. For example, as the pig's blood glucoseconcentration increased (due to infusion of glucose), so did the testmeasurements, reaching about 550 mg/dl at about 12:20. Similarly, as thepig's blood glucose concentration decreased (due to infusion ofinsulin), so did the test measurements, decreasing to about 50 mg/dl atabout 14:45.

From these data, it was concluded that a glucose sensor system of thepreferred embodiments (including a valve as described with reference toFIGS. 8A to 8C) accurately and sensitively measures intravenous glucoseconcentration over a wide dynamic range.

Example 4 Glucose Sensor System with Flow Control Device Trial in Humans

Referring now to FIG. 14, a glucose sensor, constructed as described inExample 3, and an integrated sensor system (as described in Example 3)were tested in a volunteer, diabetic host. The flow control device wasconfigured as shown in FIGS. 8A-8C. The system was configured toalternate between a calibration phase and a blood glucose measurementphase, as described elsewhere herein. At sensor/catheter initialization,a 0 mg/dl glucose saline solution filled syringe was injected into theIV tubing and the fluids bag including 100 mg/dl glucose heparinizedsaline solution was subsequently coupled to the tubing. The system wasthen turned on (e.g., sensor initialized). The 0 mg/dl glucose salinesolution passed over the sensor, after which the 100 mg/dl glucoseheparinized saline solution subsequently passed over the sensor allowingfor initial calibration information to be collected. The system,including a flow control device as described with reference to FIGS. 8Ato 8C, then oscillated between exposure of the sensor to a blood sampleand exposure of the sensor to the 100 mg/dl glucose heparinized salinesolution. The sensor auto-calibrated by a combination of calibrationinformation obtained from measurement of the 0 mg/dl-glucose and 100mg/dl-glucose saline solutions and the step-change-response of thesensor to the blood sample, according to the methods described in thesection entitled “Systems and methods for Processing Sensor Data.” Noexternal measurements (e.g., blood glucose measurements by YSI or fingerstick) were used to calibrate the system in this example. During theexperiment, the flow control device cycled between step one (measuringthe 100 mg/dl-glucose solution) and step two (blood sample take up andmeasuring the blood glucose concentration), such that one cycle wascompleted every 5-minutes. The experiment was conducted for a period ofabout 2.5 days. The host followed her usual schedule of meals andinsulin injections.

FIG. 14 is a graphical representation showing calibrated venous bloodglucose sensor measurements (test, black dots) and corresponding controlblood glucose measurements (YSI, large circles) over time in thevolunteer diabetic host. Glucose concentration is shown on the Y-axisand time on the X-axis. Test measurements tracked closely with controlmeasurements, ranging from about 350 mg/dl, at about 10:00 and about15:30, to about 50 mg/dl, at about 11:45. From these data, it has beenconcluded that 1) the sensor calibration methods of the preferredembodiments accurately calibrate the sensor and 2) the glucose sensorsystem of the preferred embodiments accurately measures intravenousglucose concentration over a wide dynamic range, for two or more days,in humans.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S. Pat.No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No. 6,558,321; U.S.Pat. No. 6,931,327; U.S. Pat. No. 6,862,465; U.S. Pat. No. 7,074,307;U.S. Pat. No. 7,081,195; U.S. Pat. No. 7,108,778; and U.S. Pat. No.7,110,803.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PatentPublication No. US-2005-0176136-A1; U.S. Patent Publication No.US-2005-0251083-A1; U.S. Patent Publication No. US-2005-0143635-A1; U.S.Patent Publication No. US-2005-0181012-A1; U.S. Patent Publication No.US-2005-0177036-A1; U.S. Patent Publication No. US-2005-0124873-A1; U.S.Patent Publication No. US-2005-0115832-A1; U.S. Patent Publication No.US-2005-0245799-A1; U.S. Patent Publication No. US-2005-0245795-A1; U.S.Patent Publication No. US-2005-0242479-A1; U.S. Patent Publication No.US-2005-0182451-A1; U.S. Patent Publication No. US-2005-0056552-A1; U.S.Patent Publication No. US-2005-0192557-A1; U.S. Patent Publication No.US-2005-0154271-A1; U.S. Patent Publication No. US-2004-0199059-A1; U.S.Patent Publication No. US-2005-0054909-A1; U.S. Patent Publication No.US-2005-0112169-A1; U.S. Patent Publication No. US-2005-0051427-A1; U.S.Patent Publication No. US-2003-0032874-A1; U.S. Patent Publication No.US-2005-0103625-A1; U.S. Patent Publication No. US-2005-0203360-A1; U.S.Patent Publication No. US-2005-0090607-A1; U.S. Patent Publication No.US-2005-0187720-A1; U.S. Patent Publication No. US-2005-0161346-A1; U.S.Patent Publication No. US-2006-0015020-A1; U.S. Patent Publication No.US-2005-0043598-A1; U.S. Patent Publication No. US-2003-0217966-A1; U.S.Patent Publication No. US-2005-0033132-A1; U.S. Patent Publication No.US-2005-0031689-A1; U.S. Patent Publication No. US-2004-0186362-A1; U.S.Patent Publication No. US-2005-0027463-A1; U.S. Patent Publication No.US-2005-0027181-A1; U.S. Patent Publication No. US-2005-0027180-A1; U.S.Patent Publication No. US-2006-0020187-A1; U.S. Patent Publication No.US-2006-0036142-A1; U.S. Patent Publication No. US-2006-0020192-A1; U.S.Patent Publication No. US-2006-0036143-A1; U.S. Patent Publication No.US-2006-0036140-A1; U.S. Patent Publication No. US-2006-0019327-A1; U.S.Patent Publication No. US-2006-0020186-A1; U.S. Patent Publication No.US-2006-0020189-A1; U.S. Patent Publication No. US-2006-0036139-A1; U.S.Patent Publication No. US-2006-0020191-A1; U.S. Patent Publication No.US-2006-0020188-A1; U.S. Patent Publication No. US-2006-0036141-A1; U.S.Patent Publication No. US-2006-0020190-A1; U.S. Patent Publication No.US-2006-0036145-A1; U.S. Patent Publication No. US-2006-0036144-A1; U.S.Patent Publication No. US-2006-0016700-A1; U.S. Patent Publication No.US-2006-0142651-A1; U.S. Patent Publication No. US-2006-0086624-A1; U.S.Patent Publication No. US-2006-0068208-A1; U.S. Patent Publication No.US-2006-0040402-A1; U.S. Patent Publication No. US-2006-0036142-A1; U.S.Patent Publication No. US-2006-0036141-A1; U.S. Patent Publication No.US-2006-0036143-A1; U.S. Patent Publication No. US-2006-0036140-A1; U.S.Patent Publication No. US-2006-0036139-A1; U.S. Patent Publication No.US-2006-0142651-A1; U.S. Patent Publication No. US-2006-0036145-A1; U.S.Patent Publication No. US-2006-0036144-A1; U.S. Patent Publication No.US-2006-0200022-A1; U.S. Patent Publication No. US-2006-0198864-A1; U.S.Patent Publication No. US-2006-0200019-A1; U.S. Patent Publication No.US-2006-0189856-A1; U.S. Patent Publication No. US-2006-0200020-A1; U.S.Patent Publication No. US-2006-0200970-A1; U.S. Patent Publication No.US-2006-0183984-A1; U.S. Patent Publication No. US-2006-0183985-A1; U.S.Patent Publication No. US-2006-0195029-A1; U.S. Patent Publication No.US-2006-0229512-A1; U.S. Patent Publication No. US-2006-0222566-A1; U.S.Patent Publication No. US-2007-0032706-A1; U.S. Patent Publication No.US-2007-0016381-A1; U.S. Patent Publication No. US-2007-0027370-A1; U.S.Patent Publication No. US-2007-0027384-A1; U.S. Patent Publication No.US-2007-0032717-A1; and U.S. Patent Publication No. US-2007-0032718 A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/515,342filed Sep. 1, 2006 and entitled “SYSTEMS AND METHODS FOR PROCESSINGANALYTE SENSOR DATA”; U.S. application Ser. No. 11/654,135 filed Jan.17, 2007 and entitled “POROUS MEMBRANES FOR USE WITH IMPLANTABLEDEVICES”; U.S. application Ser. No. 11/675,063 filed Feb. 14, 2007 andentitled “ANALYTE SENSOR”; U.S. application Ser. No. 11/543,734 filedOct. 4, 2006 and entitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUSANALYTE SENSOR”; U.S. application Ser. No. 11/654,140 filed Jan. 17,2007 and entitled “MEMBRANES FOR AN ANALYTE SENSOR”; U.S. applicationSer. No. 11/654,327 filed Jan. 17, 2007 and entitled “MEMBRANES FOR ANANALYTE SENSOR”;U.S. application Ser. No. 11/543,396 filed Oct. 4, 2006and entitled “ANALYTE SENSOR”; U.S. application Ser. No. 11/543,490filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S. application Ser.No. 11/543,404 filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S.application Ser. No. 11/681,145 filed Mar. 1, 2007 and entitled “ANALYTESENSOR”; and U.S. application Ser. No. 11/690,752 filed Mar. 23, 2007and entitled “TRANSCUTANEOUS ANALYTE SENSOR”.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

1. A method for measuring a concentration of an analyte in a vein of ahost, the method comprising: passing a reference solution at a flow rateof from about 0.001 ml/min to about 0.02 ml/min past an analyte sensorconfigured to measure an analyte concentration, wherein the analytesensor is a component of an analyte measuring system comprising avascular access device, the analyte sensor, and electronics operativelyconnected to the analyte sensor and configured to generate a signalassociated with the analyte concentration, wherein the analyte sensorresides within the vascular access device, and wherein the vascularaccess device and the analyte sensor are in fluid communication with avein of a host; measuring a signal associated with an analyteconcentration of the reference solution; drawing back a sample from thevein of the host; and measuring a signal associated with an analyteconcentration of the sample.
 2. The method of claim 1, wherein theanalyte is glucose, and wherein measuring the concentration of theanalyte comprises measuring a glucose concentration.
 3. The method ofclaim 1, further comprising repeating passing and drawing.
 4. The methodof claim 3, wherein repeating is at least one of periodically repeatingor intermittently repeating.
 5. The method of claim 1, furthercomprising calibrating the analyte sensor using a baseline measurementobtained from the signal associated with the analyte concentration ofthe reference solution.
 6. The method of claim 1, further comprisingcalibrating the analyte sensor using a sensitivity measurement obtainedfrom the signal associated with the analyte concentration of thereference solution.
 7. The method of claim 1, wherein the vascularaccess device and the analyte sensor are configured for fluidcommunication with a central vein of the host.
 8. The method of claim 1,wherein drawing back a sample comprises drawing back a sample at a flowrate of from about 0.001 ml/min to about 2 ml/min.
 9. A method formeasuring a concentration of an analyte in a vein of a host, the methodcomprising: passing a reference solution at a first flow rate controlledby a flow control device past an analyte sensor configured to measure ananalyte concentration, wherein the analyte sensor is a component of ananalyte measuring system comprising a vascular access device, theanalyte sensor, and electronics operatively connected to the analytesensor and configured to generate a signal associated with the analyteconcentration, wherein the analyte sensor resides within the vascularaccess device, and wherein the vascular access device and the analytesensor are in fluid communication with a vein of a host; measuring asignal associated with an analyte concentration of the referencesolution; drawing back a sample from the vein of the host at a secondflow rate of from about 0.001 ml/min to about 2 ml/min; and measuring asignal associated with an analyte concentration of the sample, whereinthe second flow rate is different from the first flow rate.
 10. Themethod of claim 9, wherein the second flow rate is from about 0.02ml/min to about 0.35 ml/min.
 11. The method of claim 9, wherein drawingback a sample comprises substantially blocking mixing of the referencesolution and the sample.
 12. The method of claim 9, wherein drawing backa sample comprises drawing back a sample volume of from about 1 μl toabout 2 ml from the vein.
 13. The method of claim 9, wherein the analyteis glucose, and wherein measuring the concentration of the analytecomprises measuring a glucose concentration.
 14. The method of claim 9,further comprising repeating passing and drawing.
 15. The method ofclaim 14, wherein repeating is at least one of periodically repeating orintermittently repeating.
 16. The method of claim 9, further comprisingcalibrating the analyte sensor using a baseline measurement obtainedfrom the signal associated with the analyte concentration of thereference solution.
 17. The method of claim 9, further comprisingcalibrating the analyte sensor using a sensitivity measurement obtainedfrom the signal associated with the analyte concentration of thereference solution.
 18. The method of claim 9, wherein the vascularaccess device and the analyte sensor are configured for fluidcommunication with a central vein of the host.
 19. The method of claim9, wherein the first flow rate is from about 0.25 μl/min to about 10ml/min.
 20. The method of claim 9, wherein the first flow rate is fromabout 0.001 ml/min to about 2 ml/min.
 21. A method for measuring aconcentration of an analyte in a circulatory system of a host, themethod comprising: passing a reference solution past an analyte sensorconfigured to measure an analyte concentration, the analyte sensorcomprising a component of an analyte measuring system comprising avascular access device, the analyte sensor, and electronics operativelyconnected to the analyte sensor and configured to generate a signalassociated with the analyte concentration, wherein the analyte sensorresides within the vascular access device, and wherein the vascularaccess device and the analyte sensor are in fluid communication with acirculatory system of a host; measuring a signal associated with ananalyte concentration of the reference solution; drawing back a samplefrom the circulatory system; and measuring a signal associated with ananalyte concentration of the sample, wherein the analyte measuringsystem further comprises a flow control device, wherein the flow controldevice is configured to meter flow during passing and drawing, andwherein the flow control device comprises a valve having a first pinchposition and a second pinch position, wherein the first pinch positionand the second pinch position are configured to at least partially pinchat least a portion of a tubing through which at least one of thereference solution is passed or the sample is drawn.
 22. The method ofclaim 21, wherein passing a reference solution comprises moving thevalve from the first position to the second position.
 23. The method ofclaim 21, wherein drawing back a sample comprises moving the valve fromthe second position to the first position.
 24. The method of claim 21,further comprising keeping the vein open by metering a flow of thereference solution through the vascular access device at a predeterminedrate.
 25. The method of claim 24, wherein metering the flow iscontrolled at least in part by a timing of the valve movement betweenthe first position and the second position.
 26. The method of claim 21,wherein the valve meters a volume of at least one of the referencesolution or the sample of from about 1 μl to about 2 ml during movementbetween the first pinch position and the second pinch position.
 27. Themethod of claim 21, wherein the valve meters a flow of at least one ofthe reference solution and the sample at a flow rate of from about 0.001ml/min to about 2 ml/min during movement between the first pinchposition and the second pinch position.
 28. The method of claim 21,wherein the valve is a rotating pinch valve.
 29. A method for measuringa concentration of an analyte in a circulatory system of a host, themethod comprising: passing a reference solution past an analyte sensorconfigured to measure an analyte concentration, wherein the analytesensor is a component of an analyte measuring system comprising avascular access device, the analyte sensor, and electronics operativelyconnected to the analyte sensor and configured to generate a signalassociated with the analyte concentration, wherein the analyte sensorresides within the vascular access device, and wherein the vascularaccess device and the analyte sensor are in fluid communication with acirculatory system of a host; measuring a signal associated with ananalyte concentration of the reference solution; drawing back a samplefrom the circulatory system; and measuring a signal associated with theanalyte concentration of the sample, wherein the analyte measuringsystem further comprises a flow control device, wherein the flow controldevice comprises a valve comprising a first discrete position and asecond discrete position, wherein the valve is configured to meter flowin a first direction during passing and in a second direction oppositeto the first direction during drawing, wherein drawing back a samplecomprises drawing back a sample volume of about 500 microliters or lessduring movement of the valve from the second discrete position to thefirst discrete position.
 30. The method of claim 29, wherein a samplevolume of about 300 microliters or less is drawn back.